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Diabetes Drug Discovery & Development

2017-11-182018-03-092018-02-09
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The 2018 agenda is currently being formed.

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BELOW IS THE AGENDA FROM 2017.

2017 Agenda
Day 1 - Wednesday, April 5th, 2017
7:30
Continental Breakfast & Registration
8:15
Opening Remarks
10:00
Morning Networking Break
Going Back to the Basics – Street Light Effect
Moderator: Larry Steinman, Stanford University
10:30
Antigen Specific Tolerance for Type 1 Diabetes
 
Larry Steinman
Larry Steinman
Professor, Pediatrics and Neurology
Stanford University
About Speaker: Steinman is Professor of Neurology, Neurological Sciences and Pediatrics at Stanford University and Chair of the Stanford Program in Immunology from 2001 to 2011. His research focuses on what provokes relapses and remissions in multiple sclerosis (MS... Read Full Bio 
 
 
Larry Steinman
Professor, Pediatrics and Neurology
Stanford University
 
About Speaker:

Steinman is Professor of Neurology, Neurological Sciences and Pediatrics at Stanford University and Chair of the Stanford Program in Immunology from 2001 to 2011. His research focuses on what provokes relapses and remissions in multiple sclerosis (MS) and in neuromyelitis optica (NMO) and the quest for antigen specific therapy. He and colleagues have advanced an antigen specific therapy in type 1 diabetes to Phase 2b.  He is also developing a small molecule therapeutic in trials for Huntington’s Disease. Steinman identified guardian molecules in brain that have protective properties in a number of inflammatory conditions.  These protective molecules activate regulatory B cells. 

Steinman was senior author on the 1992 Nature article that led to the drug Tysabri, approved for MS and Crohn’s disease.

Dr. Steinman graduated from Dartmouth College, Magna Cum Laude in Physics. His MD is from Harvard Medical School.  He was a post-doctoral fellow in chemical immunology fellow at the Weizmann Institute of Science. After neurology residency he remained on the faculty in 1980.  He has received numerous honors, including the John M. Dystel Prize in 2004, the Javits Neuroscience Investigator Award from the NINDS twice, the Charcot Prize in MS research, and the Cerami Prize in Translational Medicine. Steinman is a member of the National Academy of Sciences, and the National Academy of Medicine.

 
Abstract: We know the key components that are targeted by adaptive immunity in type 1 diabetes.  Why are attempts at antige...Read More 

We know the key components that are targeted by adaptive immunity in type 1 diabetes.  Why are attempts at antigen specific tolerance so rarely taken into the clinic.  A phase 2A trial with a plasmid engineered to tolerize to proinsulin was completed in a multi-center placebo controlled trial.  There was a rise in C-peptide during the period of 12 weekly doses, with a concomitant lowering of HgbA1c.  Quantum dot studies using flow cytometry indicate that as C-peptide increased, CD8 T cells specific for proinsulin fell. There were no changes in CD8 T cells to other islet antigens or to viral antigens.  A Phase 2b study will be presented as we continue progress on this front.  The promise of antigen specific tolerance in type 1 diabetes will be discussed in relationship to other ongoing programs across the globe.

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11:10
Technology in Science Does Not Always Bring innovation and Discovery; The Human Factor is the Key to Success
 
Bruno Doiron
Bruno Doiron
Assistant Professor
University of Texas Health Science Center at San Antonio
About Speaker: Bruno Doiron, Ph.D is a faculty member at the University of Texas Health Science at San Antonio. He received his undergraduate degree from University of Moncton, N.B. Canada and graduate degrees from University of Montreal, QC, Canada and University ... Read Full Bio 
 
 
Bruno Doiron
Assistant Professor
University of Texas Health Science Center at San Antonio
 
About Speaker:

Bruno Doiron, Ph.D is a faculty member at the University of Texas Health Science at San Antonio. He received his undergraduate degree from University of Moncton, N.B. Canada and graduate degrees from University of Montreal, QC, Canada and University of Paris Descartes, Paris, France. As project leader he has made major discoveries in the field of gene regulation by nutrients and has 4 patents on the modulation of glucose metabolism as it relates to the treatment diabetes and cancer. Dr. Doiron has extensive experience in basic research at the physiologic and molecular levels and in respective applications to the biotechnology field.    

 
Abstract: The street light effect in science is enhanced by today’s technology. Today’s fascination for new techniqu...Read More 

The street light effect in science is enhanced by today’s technology. Today’s fascination for new techniques precedes the scientific thinker. Technical skills have become the primary reason the institutions seeks to hire scientists. The researcher does not think by themselves now; the institution gives them a strategic guide to follow for professional advancement in research. Nevertheless, scientific discovery is not reducible to the technique. Scientific discovery only happens in the context of new ideas and concepts. Technology is the instrument used to produce data, but data alone has no meaning. Big data is brilliant at detecting a correlation. Technology is a tool, not dicta trapping minds on one path. More often mapping, sequencing, proteomic core collecting data is based on determined goals imposed by institutional research and only finds what is already known. Technique prevails over novelty. Another set of thinking is needed to integrate the data knowledge produced by the technique into innovation.

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11:40
Preclinical Implication for the Cross-Regulation of Immunity and Type 2 Diabetes
 
Jongsoon Lee
Jongsoon Lee
Assistant Professor of Medicine
Joslin Diabetes Center, Harvard Medical School
About Speaker: Jongsoon Lee, Ph.D., is an Assistant Investigator in the Section on Pathophysiology and Molecular Pharmacology at the Joslin, and an Assistant Professor of Medicine at Harvard Medical School.  Dr. Lee received his BS and MS degrees from Seoul Nation... Read Full Bio 
 
 
Jongsoon Lee
Assistant Professor of Medicine
Joslin Diabetes Center, Harvard Medical School
 
About Speaker:

Jongsoon Lee, Ph.D., is an Assistant Investigator in the Section on Pathophysiology and Molecular Pharmacology at the Joslin, and an Assistant Professor of Medicine at Harvard Medical School.  Dr. Lee received his BS and MS degrees from Seoul National University in Korea. He received his Ph.D. in Biochemistry from Boston University School of Medicine. 

 
Abstract: Obesity is the major cause of the development of insulin resistance and Type 2 Diabetes. Recently, the notion that obe...Read More 

Obesity is the major cause of the development of insulin resistance and Type 2 Diabetes. Recently, the notion that obesity-induced inflammation mediates the development of insulin resistance in animal models and humans has been gaining strong support. Furthermore, numerous studies have also shown that immune cells in local tissues, in particular in visceral adipose tissue, play a major role in the regulation of obesity-induced inflammation. It has been shown that obesity disrupts the immune balance by suppressing anti-inflammatory cells (e.g., regulatory T cells [Tregs]) while simultaneously activating pro-inflammatory cells (e.g., adipose tissue macrophages [ATMs]). Many studies from the classical immunology field show that complex cross-regulating interactions between different immune cell types control inflammation. However, the roles these interactions play have not been studied extensively in the metabolism field. We have recently shown that natural killer (NK) cells play a critical role in the development of obesity-induced inflammation and insulin resistance, in part by controlling ATM activation and adipose tissue inflammation. Hence, our studies may provide important preclinical evidence for the notion that obesity-induced inflammation regulated by adipose NK cells could be a therapeutic target for the treatment of insulin resistance and Type 2 Diabetes.

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12:10
Lunch Workshop – Speaker: Judith Gorski, Crown Bioscience
12:10
Translational Platforms to Model Pre-Diabetes, Diabetes, and Diabetic Complications
 
Judith Gorski
Judith Gorski
Global Director, Scientific Engagement
Crown Bioscience Inc.
About Speaker: Dr. Judith Gorski is Global Director of Scientific Engagement at Crown Bioscience Inc., and is a pharmacologist with over 18 years of experience in drug discovery and development in a large pharmaceutical environment.  She has extensive experience i... Read Full Bio 
 
 
Judith Gorski
Global Director, Scientific Engagement
Crown Bioscience Inc.
 
About Speaker:

Dr. Judith Gorski is Global Director of Scientific Engagement at Crown Bioscience Inc., and is a pharmacologist with over 18 years of experience in drug discovery and development in a large pharmaceutical environment.  She has extensive experience in basic research and targeted drug discovery in the disease areas of type 1 and 2 diabetes, dyslipidemia, atherosclerosis, obesity, and metabolic syndrome.  Dr. Gorski has co-authored publications in Nature, Obesity, Obesity Research, Cell Metabolism, Journal of Lipid Metabolism.

Prior to joining CrownBio, Dr. Gorski’s work at Merck focused on target identification/validation and small molecule and biologics identification/optimization with the aim of recommending lead candidates for clinical development. Her primary responsibilities were to establish and validate appropriate primary, secondary and tertiary in vivo models of dyslipidemia, obesity, metabolic syndrome, and type 1 and 2 diabetes. In addition to preclinical work, Dr. Gorski has been a member of early development teams to move lead candidates into development and has collaborated across an array of disciplines, including drug safety and metabolism, pharmaceutical sciences, early clinical development, medical affairs, regulatory affairs, and commercial development.

Dr. Gorski received her Ph.D. in Neuroscience from University of Medicine and Dentistry, New Jersey.

 
Abstract: A key challenge in preclinical studies of diabetes is the lack of translational platforms that can model the various aspects of disease progression...Read More 

A key challenge in preclinical studies of diabetes is the lack of translational platforms that can model the various aspects of disease progression and associated complications.  In this talk, Dr. Gorski will present the development and utility of CrownBio’s unique continuum of translational platforms that model various aspects of diabetes and metabolic syndrome, and how such platforms are used to predict the efficacy and safety of anti-diabetic therapies in humans.  Attendees will learn about:

  • The latest rodent and Non-Human Primate translational models of to study diabetes pathology
  • Modeling prediabetes, diabetes progression, and associated complications (e.g., nephropathy) in these models;
  • Examples of how these models are used in anti-diabetes drug development
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Novel Therapeutic Targets & Strategies
Moderator: Felicia Pagliuca, Semma Therapeutics
1:25
Is Fibroblast Activation Protein a Target for Treating Type-2 Diabetes
 
William Bachovchin
William Bachovchin
Professor, Department of Biochemistry
Tufts University School of Medicine
About Speaker: Dr. Bachovchin serves as Executive Vice President and Chief Scientist and member of the board of directors of Arisaph pharmaceuticals since he co-founded the company in 1999. He was also a co-founder of Point Therapeutics which was a publically trade... Read Full Bio 
 
 
William Bachovchin
Professor, Department of Biochemistry
Tufts University School of Medicine
 
About Speaker:

Dr. Bachovchin serves as Executive Vice President and Chief Scientist and member of the board of directors of Arisaph pharmaceuticals since he co-founded the company in 1999. He was also a co-founder of Point Therapeutics which was a publically traded biotechnology company prior to its merger with Dara BioSciences. Dr. Bachovchin is also Professor of Biochemistry at Tufts University School of Medicine.

Dr Bachovchin received a BS degree in Biology from Wake Forest University a doctoral degree in Chemistry from The California Institute of Technology, and did postdoctoral work at Harvard Medical School before arriving at Tufts. Dr. Bachovchin is an author on more than 100 peer reviewed journal articles, and an inventor on more than 30 issued patents as well as numerous pending applications. Dr. Bachovchin is a leader in the areas of NMR spectroscopy, enzymes mechanisms and drug design and discovery, especially in areas pertaining to the post proline cleaving family of enzymes. To date three drugs designed by Dr. Bachovchin have entered human clinical trials and several more are in late stage preclinical testing.

 
Abstract: Fibroblast Activating Protein (FAP) is post proline cleaving serine protease with sequence, three dimensional structur...Read More 

Fibroblast Activating Protein (FAP) is post proline cleaving serine protease with sequence, three dimensional structure and substrate specificity very similar to that of dipeptidyl amino peptidase type 4 (DPP4), which is a validated target for the treatment of diabetes.  Although FAP resembles DPP4 in ability to cleave GLP-1, this activity does not seem to be as biologically significant for FAP as for DPP4, perhaps because FAP occurs in much lower amounts than DPP4.   Recently, FAP has been reported to cleave and limit the lifetime of human, but not mouse FGF-21, suggesting that FAP inhibitors should have anti diabetic activity in humans, even if perhaps not in mice.  However, new evidence indicates that FAP may also function to limit the lifetime of mouse FGF-21 through a different cleavage and mechanism than for human FGF-21. That an FAP knockout mouse has been reported to have improved glucose tolerance, resistance to diet induced obesity and resistance to dyslipidemia, lends some support to the mouse FGF-21 hypothesis, but also that it could be limiting the lifetime of other anti diabetic peptides that could make it a new target for the treatment of type 2 diabetes.  This talk will review and critically evaluate the existing evidence implicating FAP as such a target and present some new results that test this hypothesis.

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1:50
Targeting Islet Amyloid Polypeptide (IAPP) as an Immunotherapy For Type 2 Diabetes
 
Robin Barbour
Robin Barbour
Senior Director Antibody and Assay Development
Prothena Biosciences Inc.
About Speaker: Robin has over 25 years of experience developing antibodies for both misfolded proteins and cell adhesion molecules. Currently two of these mAbs are in clinical trials, NEOD001 for AL amyloidosis and PRX002 for Parkinson’s Disease. Previously at El... Read Full Bio 
 
 
Robin Barbour
Senior Director Antibody and Assay Development
Prothena Biosciences Inc.
 
About Speaker:

Robin has over 25 years of experience developing antibodies for both misfolded proteins and cell adhesion molecules. Currently two of these mAbs are in clinical trials, NEOD001 for AL amyloidosis and PRX002 for Parkinson’s Disease. Previously at Elan, her group developed the murine version of Tysabri for Multiple Sclerosis, and Bapineuzumab for Alzheimers. In addition to antibody development, Robin’s group is responsible for the development of assays to support clinical trials including pK, ADA, Biomarker and cell based potency assays.

 
Abstract: Type 2 Diabetes is the most common form of diabetes and affects 422 million patients worldwide, with little sign of a slowing epidemic, and while t...Read More 

Type 2 Diabetes is the most common form of diabetes and affects 422 million patients worldwide, with little sign of a slowing epidemic, and while there are several classes of anti-diabetic medications available, none are disease modifying. Islet Amyloid Polypeptide (IAPP) is a 37 amino acid peptide that is co-secreted with insulin and is very prone to aggregation. IAPP deposits are found in a majority type 2 diabetes pancreata and the toxicity of insoluble and soluble aggregates are believed to contribute to the pathophysiology of type 2 diabetes. Immunotherapy studies were conducted in a transgenic rat expressing human IAPP, which presents type 2 diabetes-relevant phenotypes such as loss of pancreatic beta-cells and IAPP deposition. We first evaluated the effects of active immunization with IAPP and found even modest titers to IAPP appeared to both decrease number of animal deaths and slow the progression of the disease. Passive immunotherapy was then investigated with three antibodies targeting IAPP. IAPP immunotherapy showed significant effects on slowing increases in hemoglobin A1c and lessening changes in the Oral Glucose Tolerance Test (OGTT) compared to isotype control treated animals. Additionally, we observed decreased extracellular amyloid deposits and a trend to decreased loss of β-cells with one of the antibodies.

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2:15
Novel Mediators of Diabetes Associated Atherosclerosis
 
Sudha Biddinger
Sudha Biddinger
Associate Professor of Pediatrics
Children's Hospital of Boston
About Speaker: Dr. Biddinger is an Associate Professor of Pediatrics at Boston Children’s Hospital/Harvard Medical School.  Her lab is focused on identifying novel targets of insulin that are relevant to the development of dyslipidemia, atherosclerosis and fatty... Read Full Bio 
 
 
Sudha Biddinger
Associate Professor of Pediatrics
Children's Hospital of Boston
 
About Speaker:

Dr. Biddinger is an Associate Professor of Pediatrics at Boston Children’s Hospital/Harvard Medical School.  Her lab is focused on identifying novel targets of insulin that are relevant to the development of dyslipidemia, atherosclerosis and fatty liver disease in the insulin resistant states of obesity and diabetes. 

Dr. Biddinger performed her undergraduate studies at Princeton University and obtained her MD/PhD from the Johns Hopkins School of Medicine.  She completed her internship, pediatrics residency, and fellowship in pediatric endocrinology at Boston Children’s Hospital. 

 
Abstract: Using microarray and metabolomics approaches, we have identified the enzyme flavin mono-oxygenase 3 (FMO3) and its pro...Read More 

Using microarray and metabolomics approaches, we have identified the enzyme flavin mono-oxygenase 3 (FMO3) and its product trimethylamine-N-oxide (TMAO) as novel targets of insulin.  In the absence of normal insulin signaling, FMO3 and TMAO are increased.  We further show that knockdown of FMO3 prevents the development of hyperglycemia, hypercholesterolemia and atherosclerosis in insulin resistant mice.  These data suggest that the FMO3/TMAO pathway may yield novel targets for the treatment of diabetes, and the prevention of its complications. 

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2:40
Specialized Pro-Resolving Mediators: Novel Lipid Mediators in the Resolution Of Inflammation
 
Raja-Elie Abdulnour
Raja-Elie Abdulnour
Instructor of Medicine
Brigham and Women's Hospital
About Speaker: Raja-Elie Abdulnour is a physician-scientist faculty member at Harvard Medical School and the Pulmonary and Critical Care Division of the Brigham and Women's Hospital. His research interests are centered on essential fatty acid-derived Specialized Pr... Read Full Bio 
 
 
Raja-Elie Abdulnour
Instructor of Medicine
Brigham and Women's Hospital
 
About Speaker:

Raja-Elie Abdulnour is a physician-scientist faculty member at Harvard Medical School and the Pulmonary and Critical Care Division of the Brigham and Women's Hospital. His research interests are centered on essential fatty acid-derived Specialized Pro-resolving Mediators (SPM) and their role in host defense and resolution of inflammation. He is an investigator in a NIH-funded program project grant led by Prof Charles Serhan that aims to harness SPMs and the recently discovered bioactive SPM-sulfido conjugates for resolution pharmacology. The over-arching goal is to develop novel therapies to better treat human diseases defined by uncontrolled inflammation and impaired tissue repair, such as diabetes mellitus.

 
Abstract: In health, inflammation serves to contain tissue injury and is normally self-limited. If excessive in amplitude and du...Read More 

In health, inflammation serves to contain tissue injury and is normally self-limited. If excessive in amplitude and duration, inflammation is associated with the development of metabolic diseases like diabetes mellitus. Specialized pro-resolving lipid mediators (SPMs)–resolvins, protectins, and maresins–are novel autacoids that resolve inflammation, protect organs, and restore homeostasis. Via receptor-mediated signaling, SPM terminate neutrophil recruitment, counter-regulate pro-inflammatory mediators, and stimulate efferocytosis by macrophages and tissue remodeling. Here, we review SPM physiology and their roles in counter-regulating inflammation and restoring homeostasis in diabetes. We also present evidence for a novel intra-vascular biosynthetic pathway that is organ-protective, emphasizing SPM as potential therapeutic strategies for inflammation in metabolic diseases.

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3:05
Afternoon Networking Break
What’s in the Pipeline: Pre-clinical & Clinical Strategies
Moderator: Denise Faustman, Harvard Medical School
3:35
Update on Phase II multi-dose BCG Clinical Trials for Reversal of Established Type 1 Diabetic Subjects
 
Denise Faustman
Denise Faustman
Director of the Immunobiology Laboratory at the Massachusetts General Hospital (MGH)
Associate Professor of Medicine at Harvard Medical School
About Speaker: Denise Faustman, MD, PhD, is Director of the Immunobiology Laboratory at the Massachusetts General Hospital (MGH) and an Associate Professor of Medicine at Harvard Medical School. She is currently leading a clinical trial program investigating the po... Read Full Bio 
 
 
Denise Faustman
Director of the Immunobiology Laboratory at the Massachusetts General Hospital (MGH)
Associate Professor of Medicine at Harvard Medical School
 
About Speaker:

Denise Faustman, MD, PhD, is Director of the Immunobiology Laboratory at the Massachusetts General Hospital (MGH) and an Associate Professor of Medicine at Harvard Medical School. She is currently leading a clinical trial program investigating the potential of the BCG vaccine as a disease reversal treatment for long-standing type 1 diabetes. Her research accomplishments include the first scientific description of modifying donor tissue antigens to change their foreignness, the identification of interrupted T cell education through MHC class I, and the identification of autoimmune T cell sensitivity to TNF. For both autoreactive CD8 T cells she has identified the TNFR2 receptor as central and also the TNFR2 receptor for the expansion of beneficial Treg cells.  These achievements have earned her awards including the National Institutes of Health and National Library of Medicine “Changing the Face of Medicine” Award as one of 300 American physicians (one of 35 in research) honored for seminal scientific achievements in the United States, the Oprah Achievement Award for “Top Health Breakthrough by a Female Scientist,” and the Women in Science Award from the American Medical Women’s Association and Wyeth Pharmaceutical Company.  Dr. Faustman’s research has been highlighted in publications including Science, Nature, The Wall Street Journal, The New York Times, Los Angeles Times, The London Financial Times and Scientific American. She earned her MD and PhD from Washington University School of Medicine, in St. Louis, Missouri, and completed her internship, residency, and fellowships in Internal Medicine and Endocrinology at the Massachusetts General Hospital.

 
 
Abstract: The BCG vaccine represents the most continuously used and safest vaccine in world history, first used over 100 years ago for tuberculosis preventio...Read More 

The BCG vaccine represents the most continuously used and safest vaccine in world history, first used over 100 years ago for tuberculosis prevention. Currently, 10 human clinical trials are testing repeat BCG vaccination in diverse forms of autoimmunity and allergies. Phase I study of the BCG vaccine, as two vaccines four weeks apart, in longstanding type 1 diabetics (T1D) reveals potential disease modulating effects after repeated BCG vaccinations, including death of autoreactive cells, transient and modest restoration of insulin secretion and induction of beneficial regulatory T cells (Tregs). This trial was designed for 22 weeks of intense monitoring. Global data on the efficacy of the BCG vaccine in autoimmunity, especially in new onset multiple sclerosis, suggests the full clinical effect of the vaccine develops after years;BCG prevents disease progression in Phase II multiple sclerosis trials, a benefit not mimicked by the standard of care. Based on the delay in full clinical effects of the BCG vaccine, 2 T1D clinical trials are underway to look for clinically meaningful improvements.   First, a long-term follow-up for 8 years after two BCG doses is underway. Second, a Phase II clinical trial using multi-dose BCG in longstanding T1D was initiated in June 2015 in 150 subjects with a five-year monitoring period. This double-blinded, placebo controlled immuno-interventional trial protocol was approved by the FDA and is unique in testing the efficacy of the BCG vaccine in long-term diabetic subjects (>15yrs) with small but detectable levels of C-peptide secretion.  Based on published Phase II clinical trial data of BCG in multiple sclerosis subjects, the therapeutic effects of this vaccine appear to improve over the passage of time; therefore, potential clinical benefits in the diabetes trial will be followed for 5 years. The primary endpoint of the Phase II BCG trail is decrease in HbA1c. The selection of BCG as an intervention in T1D is based on the protective host TNF response, including induction of Tregs, and potential long-term modulation of inflammatory profile of vaccinated subjects. All Phase II subjects are being monitored by RNAseq, epigenetics and Treg cell numbers and Treg signature gene expression to define the BCG mechanism.  Similar to the close pathogenic tuberculosis strain, BCG in humans systemically modifies the cytokine patterns and at least in culture, epigenetically turns on Treg cells for permanent reversal of self-reactivity.

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4:00
BPM51545 is a Novel First-in-Class Anti-Diabetic Biologic That Improves Glucose Metabolism in Skeletal Muscle
 
Pragalath Sundararajan
Pragalath Sundararajan
Scientist
BERG Health
About Speaker: Pragalath Sundararajan works as a Scientist in the Endocrinology program at BERG. He received his Bachelor of Technology in Biotechnology from Anna University, India and MS in Biotechnology from Northeastern University. Pragalath began his career at... Read Full Bio 
 
 
Pragalath Sundararajan
Scientist
BERG Health
 
About Speaker:

Pragalath Sundararajan works as a Scientist in the Endocrinology program at BERG. He received his Bachelor of Technology in Biotechnology from Anna University, India and MS in Biotechnology from Northeastern University.

Pragalath began his career at BERG five years ago and has worked on the validation of Diabetes drug targets identified by BERG’s proprietary Interrogative Biology® Platform. His work has contributed to BERG’s therapeutic pipeline which currently has multiple novel anti-diabetic biologic molecules that have progressed beyond the proof of concept phase and are in various stages of pre-clinical development. His current research efforts are focused on supporting the pre-clinical development of these molecules and in the identification of novel drug targets for Diabetes and other metabolic diseases.

 
Abstract: BERG’s proprietary Interrogative Biology® Discovery platform was used to delineate distinct molec...Read More 

BERG’s proprietary Interrogative Biology® Discovery platform was used to delineate distinct molecular signatures that drive the pathophysiology of diabetes and metabolic syndrome. Using this approach, we identified a novel anti-diabetic biologic, BPM51545, which improves glucose metabolism when delivered into skeletal muscle. A dose and time-dependent increase in the intracellular uptake of BPM51545 was observed upon treating cultured human skeletal muscle myotubes in vitro. The uptake of the enzymatically active form of BPM51545 significantly increased glucose uptake as well as glycolytic activity in myotubes and this effect was independent of insulin. In vivo, a nanoparticle system carrying a Skeletal Muscle Targeting Peptide (SMTP) was used to deliver BPM51545 to its site of action, in DIO and db/db mice. In both models, BPM51545 treatments significantly enhanced glucose tolerance without affecting body weight. Moreover, a consistent reduction in daily fed blood glucose levels was observed in db/db mice after 4 weeks of treatments. In addition, when combined with Rosiglitazone, BPM51545 treatments accelerated the time to attain blood glucose level normalization in db/db mice. This combination also lead to a significant reduction in body weight gain induced by Rosiglitazone alone treatments in db/db mice. Taken together, BPM51545 is a potent novel therapeutic biologic that can be used for treating diabetes and associated metabolic diseases.

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4:25
Diasome Pharmaceuticals’ 2017 Phase 2 and Phase 2b Clinical Trials Update
 
Robert Geho
Robert Geho
Co-Founder and Chief Executive Officer
Diasome Pharmaceuticals Inc
About Speaker: Robert Geho is co-founder and CEO of Diasome Pharmaceuticals, Inc., a privately-held developer of liver targeting systems for insulin and other drugs to treat diabetes.  Working alongside a team of nanotechnology formulation and protein chemistry ex... Read Full Bio 
 
 
Robert Geho
Co-Founder and Chief Executive Officer
Diasome Pharmaceuticals Inc
 
About Speaker:

Robert Geho is co-founder and CEO of Diasome Pharmaceuticals, Inc., a privately-held developer of liver targeting systems for insulin and other drugs to treat diabetes.  Working alongside a team of nanotechnology formulation and protein chemistry experts, highly experienced clinical research professionals, and globally recognized investors, Robert is actively involved in the clinical development of Diasome’s Hepatocyte Directed Vesicle “HDV”) system.  HDV Insulin is Phase 3-enabled and is currently being tested in a multi-center Phase 2b study in patients with Type 1 diabetes.

 
Abstract: Diasome Pharmaceuticals, Inc. is currently testing its proprietary Hepatocyte Directed Vesicle (“HDV”) tec...Read More 

Diasome Pharmaceuticals, Inc. is currently testing its proprietary Hepatocyte Directed Vesicle (“HDV”) technology in a randomized, double-blinded, six month dosing Phase 2b study in 150 subjects with Type 1 diabetes.  This study is designed to compare multiple clinical endpoints in subjects who receive either HDV + insulin lispro or lispro alone as their only pre-meal insulin therapy.  In addition, during the first half of 2017 Diasome is planning to initiate both a six week study of HDV Insulin in 40 Type 1 subjects focused on demonstrating improved glucose time in range (the “Good to Great” Study) and a first in man, randomized crossover design Phase 2 study of HDV Insulin in Type 1 subjects on insulin pumps.

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4:50
Networking Reception & Poster Session
Day - 2 Thursday, April 6th, 2017
7:30
Continental Breakfast
Joint Plenary Session: Where do We Stand with Cell Therapy in Diabetes?
Moderator: Mark Zimmerman, Viacyte
8:30
Developing Cell Therapies for Diabetes
 
Mark Zimmerman
Mark Zimmerman
Vice President, Strategy and Business Development
ViaCyte
About Speaker: Mark Zimmerman received his bachelors in Biology from Syracuse University and his masters and doctorate in Biomedical Engineering from Rutgers University. Mark joined UMD-New Jersey Medical School as an Assistant Professor in 1986 and left in 1996 as... Read Full Bio 
 
 
Mark Zimmerman
Vice President, Strategy and Business Development
ViaCyte
 
About Speaker:

Mark Zimmerman received his bachelors in Biology from Syracuse University and his masters and doctorate in Biomedical Engineering from Rutgers University. Mark joined UMD-New Jersey Medical School as an Assistant Professor in 1986 and left in 1996 as an Associate Professor of Surgery with tenure. His research interests spanned musculoskeletal tissue engineering, sports medicine, trauma, and spine biomechanics and biomaterials.

Mark joined Johnson and Johnson in 1997 as a principal scientist/group leader and transitioned into regenerative medicine projects related to orthopaedic surgery, wound healing, vascular biology, and diabetes. Mark was appointed executive director of a Lifescan incubator, BetaLogics, in July 2002. BetaLogics transitioned to a Johnson and Johnson Internal Venture in 2004. The mission of BetaLogics was to discover and develop a cellular product to treat diabetes. Mark was appointed Venture Leader/Vice President of BetaLogics, a business unit of Janssen R&D LLC in 2009. Janssen completed a business transaction with ViaCyte in 2015 and merged the assets of BetaLogics into ViaCyte. Mark is currently seconded to ViaCyte and serves as the Vice President of Strategy and Business Development.

 
Abstract: ViaCyte’s product candidates are based on the directed differentiation of pancreatic progenitor cells from human...Read More 

ViaCyte’s product candidates are based on the directed differentiation of pancreatic progenitor cells from human pluripotent stem cells. These pancreatic progenitor cells are implanted in a durable and retrievable encapsulation device. Once implanted, these cells are designed to further mature to the pancreatic endocrine cells, including beta cells, which secrete insulin and other regulatory factors in response to blood glucose levels. ViaCyte has two products in development. The PEC-Direct™ product candidate delivers the pancreatic progenitor cells in a non-immunoprotective device and is being developed for type 1 diabetes patients that have severe hypoglycemic episodes, extreme glycemic lability, and/or impaired hypoglycemia awareness. The PEC-Encap™ (also known as VC-01) product candidate delivers pancreatic progenitor cells in an immunoprotective device and is currently being evaluated in a Phase 1/2 trial in patients with type 1 diabetes who have minimal to no insulin-producing beta cell function. This presentation will describe first-hand experience with the challenges and progress in developing pluripotent stem cell-derived products, including manufacturing and quality control, methods of delivery, clinical trials, and market opportunities.

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8:55
Development of a Stem Cell Derived Pancreatic Islet Cell Therapy for Diabetes
 
Felicia Pagliuca
Felicia Pagliuca
Vice President, Cell Biology R&D
Semma Therapeutics
About Speaker: Dr. Pagliuca currently serves as Vice President of Cell Biology Research and Development and is scientific co-founder of Semma Therapeutics. She leads cell-based research and development and plays a key role in supporting Semma's preclinical, regulat... Read Full Bio 
 
 
Felicia Pagliuca
Vice President, Cell Biology R&D
Semma Therapeutics
 
About Speaker:

Dr. Pagliuca currently serves as Vice President of Cell Biology Research and Development and is scientific co-founder of Semma Therapeutics. She leads cell-based research and development and plays a key role in supporting Semma's preclinical, regulatory, and manufacturing strategies for its cell therapy products. Felicia also works closely with Semma’s senior leadership on corporate development activities, including key collaborations and partnerships. Previously, Felicia was a postdoctoral fellow in Professor Doug Melton’s laboratory at the Harvard Stem Cell Institute. Felicia was part of the team in the Melton lab that discovered how to generate stem cell derived beta cells and published a seminal paper in Cell in 2014. She is an expert in stem cell biology and diabetes and one of the inventors of Semma Therapeutics’ key technologies. Felicia received a B.S. from Duke University and a Ph.D. from Cambridge University where she was a Marshall Scholar. She is currently on leave from Harvard Business School where she was a Kaplan Fellow.

 
Abstract: Semma Therapeutics is a preclinical stage biotechnology company with the mission to transform the treatment of diabete...Read More 

Semma Therapeutics is a preclinical stage biotechnology company with the mission to transform the treatment of diabetes through development of stem cell derived pancreatic islets, including insulin-producing beta cells, to be used as a cell replacement therapy.   Diabetes results from the dysfunction and/or destruction of the insulin-producing beta cells in the pancreatic islet.  The development of replacement sources of beta cells, combined with effective methods of delivery back into the patient’s body, has the potential to “cure” the disease.  Recent breakthroughs have enabled the virtually unlimited production of replacement beta cells through pluripotent stem cell differentiation.  At Semma, we are focused on further optimization and innovation in differentiation technologies, manufacturing scale-up, and characterization of stem cell derived islets in preclinical studies in order to move into clinical trials.  In parallel, we are engineering innovative encapsulation solutions, using novel materials and device configurations, to solve the challenge of delivering and protecting these therapeutics from immune destruction.

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9:20
Tolerogenic Therapy for Type 1 Diabetes: A Phase 2 Randomized Study of Autologous Regulatory T-cells Adolescents with Recent Onset T1DM
 
Douglas Losordo
Douglas Losordo
Chief Medical Officer, Senior Vice President of Clinical, Medical & Regulatory Affairs
Caladrius Biosciences
About Speaker: Dr. Losordo is the Chief Medical Officer and Senior Vice President of Clinical, Medical and Regulatory Affairs of Caladrius Biosciences, Inc, Clinical Professor of Medicine at  the New York University Langone Medical Center  and Adjunct Professor o... Read Full Bio 
 
 
Douglas Losordo
Chief Medical Officer, Senior Vice President of Clinical, Medical & Regulatory Affairs
Caladrius Biosciences
 
About Speaker:

Dr. Losordo is the Chief Medical Officer and Senior Vice President of Clinical, Medical and Regulatory Affairs of Caladrius Biosciences, Inc, Clinical Professor of Medicine at  the New York University Langone Medical Center  and Adjunct Professor of Medicine at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Dr. Losordo’s career has been dedicated to patient care and to the development of novel therapeutics aimed at the reversal or repair of chronic conditions such as heart failure, critical limb ischemia, cancer and diabetes.

A native of Brooklyn, NY, he received his medical degree from the University of Vermont. Dr. Losordo completed an internship, residency and fellowship at St. Elizabeth’s Medical, Boston, Massachusetts, where he subsequently joined the faculty, working with the late Jeff Isner to develop a program in gene therapy and cell-based tissue repair. Dr. Losordo’s group has executed the full “translational medicine” paradigm: identifying potential therapeutic approaches in the laboratory, investigating these strategies in pre-clinical/IND-enabling models and designing and executing first-in-human and proof-of-concept clinical trials as the study sponsor/IND-holder. His work has included developing VEGF gene therapy for myocardial ischemia and diabetic neuropathy, CD34+ cell therapy for refractory angina, critical limb ischemia, severe claudication and coronary microvascular dysfunction and regulatory T cell therapy for autoimmune disease. Two of these candidates advanced to phase 3. At Caladrius Dr. Losordo has initiated a phase 2 study of autologous regulatory T cell therapy for new onset type 1 diabetes in children and recently received Japanese PMDA agreement on a study of CD34 cell therapy for critical limb ischemia targeting conditional approval under the new Japanese regulatory rules governing regenerative therapies. In addition to his own work Dr. Losordo has also mentored numerous scientists and physician-scientists from around the world who now have their own independent programs in translational research.

 
Abstract: T1DM in children is characterized by increased immune activation and a more aggressive clinical course compared to the adult population. Available ...Read More 

T1DM in children is characterized by increased immune activation and a more aggressive clinical course compared to the adult population. Available evidence suggests that adoptive transfer of regulatory T-cells (Tregs) can slow disease progression and potentially lead to remission. Previous phase 1 clinical trials have demonstrated that expanded polyclonal Tregs are safe and well tolerated in both adults and children, supporting the development of a phase 2 trial to assess safety and efficacy of Treg therapy for T1DM in adolescents.

Caladrius Biosciences has launched a phase 2, double-blind, placebo-controlled, multi-center clinical trial to assess the safety and efficacy of autologous Tregs  to modify the T1DM disease course, including preservation of β-cell function and improvements in disease severity in adolescents (aged 8 to 17 years) with recent onset T1DM.

Approximately 111 subjects will be randomized to one of 3 treatment groups in a 1:1:1 ratio (placebo, 2.5 or 20 million Treg cells/kg BW). Key endpoints include the 2-hour and 4-hour Mixed Meal Tolerance Test (MMTT) stimulated C-peptide AUC at various time points through 24 months, daily dose of insulin use, severe hypoglycemia, and the percentage of subjects achieving partial or complete T1DM remission. Subjects will be followed for 2 years. A safety review has been conducted after the initial 19 subjects were followed for 3 months. An interim analysis is planned after approximately 50% of subjects complete the Week 26 visit. Extensive immune-profiling will be performed before and after Treg vs placebo infusion

This phase 2 study will advance insight into the safety and potential efficacy of adoptive transfer of Tregs to modify the T1DM disease course in children with recent onset T1DM as well as providing unprecedented insights into immune regulatory function.

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9:45
Mesenchymal Stromal Cells as Cellular Therapeutics to Enhance Human Pancreatic Islet Transplantation in Type-1 Diabetes
 
John Campbell
John Campbell
Associate Director, Research, Development & Innovation
SNBTS, National Science Laboratory
About Speaker: Professor John Campbell is Associate Director of Research and Development at the Scottish National Blood Transfusion Service (SNBTS) in Edinburgh. He completed his PhD in Pathology at Edinburgh in 1995 on the immunopathogenesis of lymproliferative di... Read Full Bio 
 
 
John Campbell
Associate Director, Research, Development & Innovation
SNBTS, National Science Laboratory
 
About Speaker:

Professor John Campbell is Associate Director of Research and Development at the Scottish National Blood Transfusion Service (SNBTS) in Edinburgh. He completed his PhD in Pathology at Edinburgh in 1995 on the immunopathogenesis of lymproliferative disease, and has worked in the cellular therapy field for over 20 years in academic and industry positions. He is currently the national head of research for SNBTS and holds academic appointments at the Universities of Glasgow and Edinburgh. SNBTS has a substantial cellular therapy research programme, with over 40 full time scientists working on basic cellular function; translation of laboratory protocols to full GMP processes; and production of cellular therapeutics for treatment of patients. SNBTS has a dedicated, fully MHRA licensed, GMP cellular therapy production centre at the Scottish Centre for Regenerative Medicine. This GMP manufacturing and development capacity will be substantially increased when SNBTS moves to the Jack Copland Centre, Edinburgh, in early 2017. Cellular therapeutics in development and early phase clinical trials include, mesenchymal stromal cells, corneal limbal stem cells, macrophages for tissue repair and virus -specific T Lymphocytes.

 
Abstract: Islet transplantation is of proven efficacy in subjects with Type 1 diabetes where glycaemic control is problematic, s...Read More 

Islet transplantation is of proven efficacy in subjects with Type 1 diabetes where glycaemic control is problematic, stabilizing glycaemic control and restoring awareness of hypoglycaemia where this has been compromised. However, long term graft survival remains poor and patients typically require two to three islet transplants. Innate and adaptive immune responses contribute to early and ongoing graft attrition. Therapeutic strategies to improve graft function are urgently needed. Ideally, a therapeutic strategy would modulate the inflammatory and immune response and enhance engraftment of islets. Mesenchymal stromal cells (MSCs) are multipotent cells found in the majority of tissues and have been shown to support regeneration of tissues by supporting blood vessel formation through a broad spectrum of growth factors and extracellular matrix secreted. This tissue building function is accompanied by the ability to suppress T cell responses and modulate inflammatory infiltration. We have investigated the ability of GMP-grade human MSC to support human Islet engraftment and function in vivo pre-clinical models. In this presentation we will discuss the properties of MSC from different source tissues and how they can be used to support and improve islet graft function.

Learning outcomes:
– Understanding the impact of islet transplantation on the health of patients with severe Type-1 Diabetes
– Understanding the function of Mesenchymal Stromal Cells as cellular therapeutics, including the challenges of GMP manufacturing
– In vivo models of human islet transplantation – what can be learned and what are the limitations
– Measuring the improvement in transplant function when co-transplanted with cellular therapeutics

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10:10
Morning Networking Break
11:25
Lunch on Your Own
Day - 3 Thursday, November 16th, 2017
8:00
Registration & Breakfast at Restaurant (included for those staying at the Radisson Blu)
8:50
Welcome & Opening Remarks
10:55
Morning Networking Break
Tools and Technologies for Drug Discovery
Moderator: Ingo Mugge, Alkermes
11:25
Medicinal Chemistry Optimizations in Deep Water: SAR Studies on mGluR5 Allosteric Modulators
 
György  Keserű
György Keserű
Principal Investigator, Medicinal Chemistry
Hungarian Academy of Sciences
About Speaker: György M. Keserű obtained his Ph.D. at Budapest, Hungary and joined Sanofi-Aventis CHINOIN heading a chemistry research lab. He moved to Gedeon Richter in 1999 as the Head of Computer-aided Drug Discovery. He earned D.Sc. from the Hungarian Academy... Read Full Bio 
 
 
György Keserű
Principal Investigator, Medicinal Chemistry
Hungarian Academy of Sciences
 
About Speaker:

György M. Keserű obtained his Ph.D. at Budapest, Hungary and joined Sanofi-Aventis CHINOIN heading a chemistry research lab. He moved to Gedeon Richter in 1999 as the Head of Computer-aided Drug Discovery. He earned D.Sc. from the Hungarian Academy of Science in 2003 and he was invited for a research professorship at the Budapest University of Technology and Economics. Since 2007 he was appointed as the Head of Discovery Chemistry at Gedeon Richter. He served as a director general of the Research Centre for Natural Sciences (RCNS) at the Hungarian Academy of Sciences. He contributed to the discovery of the antipsychotic Vraylar® (cariprazine) that has been approved by the US FDA in 2015 and marketed in the US from 2016. From 2015 he is heading the Medicinal Chemistry Research Group at RCNS. His research interests include medicinal chemistry, drug design, and in silico ADME. He has published over 200 papers and more than 10 books and book chapters.

 
Abstract: Potency optimizations are typically involving the formation of new interactions between the ligand and its protein target. In many cases, however, ...Read More 

Potency optimizations are typically involving the formation of new interactions between the ligand and its protein target. In many cases, however, ligand-protein interactions are water mediated that makes SAR analyses extremely. This situation could be even more challenging when the potency gain is mostly traced back to the displacement of energetically unfavoured waters and/or the perturbation of water networks in the binding pocket. Targeting functional water channels as allosteric sites in GPCRs is a typical example for such a challenging optimization. As a prototype study we investigate different mGluR5 NAM programs analysing the optimization path and SAR in the context of water mediated interactions formed during the potency optimization of these chemotypes. The optimization of allosteric mGluR5 ligands is notoriously difficult and is complicated by minor structural changes induced NAM-PAM switch. The allosteric site of the mGlu5 receptor is located in a functional water channel. The binding pocket is therefore occupied by water molecules that are at least partially ordered and play a role in signal transduction. The perturbation of this water network by allosteric ligands contributes significantly to the observed ligand affinity and functional activity. This phenomenon severely compromises the success of SAR studies. We show that an improved interpretation of SAR can be achieved by considering the reorganization of the water network upon complex formation. Ligand binding leads to the expulsion of water molecules and the free-energy consequence of the binding is affected by this process. Moreover, ligand binding changes the free-energy of the water network that remains in the binding pocket and the effect of this perturbation can also significantly influence the observed ligand affinity. The importance of the water molecules is therefore also reflected by the difference in the free-energy change of the water network corresponding to the binding of ligands as their activity improves from micromolar to high nanomolar. This observation supports that ligand-protein interactions are not the only factors and even they are not decisive for the binding of these ligands. However, the presence of a favourable water network and optimized ligand-protein interactions are both required to achieve high activity on mGluR5 receptor.

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11:50
High Content Analysis-Based Exploration of Steroid Receptor Functions
 
Michael Mancini
Michael A. Mancini
Professor, Molecular and Cellular Biology
Baylor College of Medicine
About Speaker: The Mancini lab focuses upon single cell analysis of steroid receptor functions, primarily estrogen and androgen receptors (ER, AR), and attendant coregulators. Our HCA/HCS-based projects explore cell signaling, endocrine disrupting chemicals and epi... Read Full Bio 
 
 
Michael A. Mancini
Professor, Molecular and Cellular Biology
Baylor College of Medicine
 
About Speaker:

The Mancini lab focuses upon single cell analysis of steroid receptor functions, primarily estrogen and androgen receptors (ER, AR), and attendant coregulators. Our HCA/HCS-based projects explore cell signaling, endocrine disrupting chemicals and epigenetics at the single cell level in engineered and native cultured cells.

 
Abstract: The Mancini lab utilizes single cell-oriented imaging studies to study transcriptional activity of primarily estrogen receptor and androgen recepto...Read More 

The Mancini lab utilizes single cell-oriented imaging studies to study transcriptional activity of primarily estrogen receptor and androgen receptors in highly multiplexed, high content assays/screens.  The lab has developed high throughput microscopy and image informatics approaches to study receptor functions, including a program to evaluate and classify endocrine disrupting chemicals (EDCs), including bisphenol A and analogs thereof.  The overall high content analysis-based screening approaches have been used to also perform mRNA FISH for receptor targets, and nuclear receptor coregulator siRNA screens that identified a novel ubiquitin ligase as a key regulator of ER functions.  High throughput approaches have also been used to better enable monoclonal antibody development, including use of HCA to identify hits in primary hybridoma screens using conditions of the desired end assay (e.g., immunofluorescence, IHC, mRNA FISH, immunogold, etc), greatly surpassing the value of ELISA-driving screening.  

Benefits:
1. learn about benefits of single cell analysis in transcription assays
2. learn about issues of heterogeneity (transcription factor levels vs transcriptional output)
3. learn about sensitive, multiplexed endocrine disrupting chemical assays
4. learn about epigenetic issues that are linked to how many endogenous large gene alleles actively respond to hormone

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12:15
Halogen-Enriched Fragment Libraries (HEFLibs) - A Tool for Studying Halogen Bonding
 
Frank  Boeckler
Frank Boeckler
Professor, Pharmacy and Biochemistry
Eberhard Karls Universität Tübingen
About Speaker: Frank M. Boeckler received his Ph.D. in Medicinal Chemistry at the University of Erlangen (Germany) in 2004 under supervision of Prof. Peter Gmeiner. He specialized in computational chemistry and drug design, ranging from QM methods to in silico scre... Read Full Bio 
 
 
Frank Boeckler
Professor, Pharmacy and Biochemistry
Eberhard Karls Universität Tübingen
 
About Speaker:

Frank M. Boeckler received his Ph.D. in Medicinal Chemistry at the University of Erlangen (Germany) in 2004 under supervision of Prof. Peter Gmeiner. He specialized in computational chemistry and drug design, ranging from QM methods to in silico screening. In 2006, he joined Prof. Sir Alan R. Fersht at the MRC Center for Protein Engineering in Cambridge/UK as Marie Curie fellow and discovered there p53 mutant stabilizers as potential new cancer therapeutics. While working in Cambridge at the interface of experiment and theory, he focused on molecular biology and biophysics. In 2008, he was appointed as Professor (W2tt) for Bioanalytics at Ludwig-Maximilians University (LMU) Munich. In 2010, he moved to Eberhard Karls University Tuebingen as Professor for Medicinal Chemistry/Drug Design. He is head of the laboratory of Molecular Design & Pharmaceutical Biophysics, which combines chemical biology, molecular and structural biology and biophysics, as well as computational chemistry and molecular design. His work is dedicated to understanding molecular interactions as the foundation for chemical biology and drug discovery, to apply theoretical and biophysical methods to cancer research, and to develop novel peptide-based toolkits. Since 2014, he is also member of the Center of Bioinformatics (ZBIT) of the University of Tuebingen. In 2015 he has joined the team of editors of the RÖMPP Encyclopedia covering the area of Pharmacy and Medicine. He has received multiple awards, including the Klaus-Grohe prize in Medicinal Chemistry, as well as the European Federation of Medicinal Chemistry (EFMC) Young Medicinal Chemist in Academia Prize (2016).

 
Abstract: With the popularity of halogen bonding on the rise, particularly in life sciences and drug discovery [1], there is an increasing demand for underst...Read More 

With the popularity of halogen bonding on the rise, particularly in life sciences and drug discovery [1], there is an increasing demand for understanding the complexity and versatility of these interactions. Halogen bonds are favorable, fairly directional interactions between an electropositive region on the halogen, the sigma hole, and a number of different nucleophilic interaction partners. Some aspects of halogen bonding are not yet understood well enough to take full advantage of its potential in drug discovery. In this talk, I will present the concept of halogen-enriched fragment libraries (HEFLibs). These libraries consist of chemical probes, facilitating the identification of favorable halogen bonds by sharing the advantages of classical fragment-based screening. We have applied the HEFLibs concept to finding p53 mutant stabilizers [2], yielding a series of molecular probes that show a robust binding mode featuring one of the strongest halogen bonds towards a backbone carbonyl in the entire PDB [3]. In order to optimize the diversity of HEFLibs, we have invented a feature tree-based similarity assessment guiding the diversification of fragment chemotypes, binding motifs and halogen bonding strengths. We achieve a fast and efficient implementation of tuning effects into the diversity selection by a machine-learned model. Such diversity-optimized HEFLibs are valuable tools for studying the strength and tunability of halogen bonds, while likewise allowing to investigate chemical and metabolic stability in a scaffold-dependent and substituent-specific manner [4]. Furthermore, binding motifs involving halogen bonds can be used for improving our understanding of cooperativity and specificity in molecular recognition processes in the binding site. Besides providing insights into the nature and applicability of halogen bonding, halogen-enriched fragment libraries provide smart starting points for hit-to-lead evolution. I will summarize some recent projects in which HEFLibs were applied to typical drug targets. References: [1] J Med Chem 2013, 56, 1363-1388. [2] J Am Chem Soc 2012, 134, 6810-6818. [3] J Chem Inf Model 2015, 55, 687-699. [4] Future Med Chem 2014, 6, 617-639.

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12:40
New Directions in DNA-Encoded Chemistry Through a Tailored Encoding Strategy
 
Andreas  Brunschweiger
Andreas Brunschweiger
Research Group Leader, Chemistry & Chemical Biology
TU Dortmund
About Speaker: Andreas Brunschweiger studied pharmacy at the University of Kiel (Germany), and joined the group of Prof. Christa Müller at the University of Bonn (Germany) to obtain his Ph.D. After conducting postdoctoral research in the same group in a collaborat... Read Full Bio 
 
 
Andreas Brunschweiger
Research Group Leader, Chemistry & Chemical Biology
TU Dortmund
 
About Speaker:

Andreas Brunschweiger studied pharmacy at the University of Kiel (Germany), and joined the group of Prof. Christa Müller at the University of Bonn (Germany) to obtain his Ph.D. After conducting postdoctoral research in the same group in a collaboration project with UCB Pharma to develop small molecule inhibitors for targets associated with neurodegenerative diseases, he joined Prof. Jonathan Hall's research group at the Institute of Pharmaceutical Sciences of the ETH Zurich (Switzerland) in 2010. There, he was involved in the the development of a chemical biology strategy to identify target RNAs of microRNAs, and the design and synthesis of oligonucleotides as microRNA inhibitors. In 2013 he took up his present position as a group leader at the Faculty of Chemistry and Chemical Biology at the TU Dortmund University. His current research interests include the development of new synthesis and encoding strategies that allow for expanding the chemical space of DNA-encoded small molecule screening libraries.

 
Abstract: DNA-encoded compound libraries (DELs) have found widespread use as screening technology for drug research.[1,2] Tagging compounds with g...Read More 

DNA-encoded compound libraries (DELs) have found widespread use as screening technology for drug research.[1,2] Tagging compounds with genetic information allows for synthesis and handling of very large screening collections of drug-like small molecules as complex mixtures. These compound mixtures are screened efficiently on disease-relevant target proteins by selection. Bioactive compounds are identified from a screen by PCR-amplification of the genetic information and next generation sequencing of the amplicon mixtures.

Heterocycles are essential structures in the chemical space of bioactive compounds. Transition metal catalysts, and acid organocatalysts enable access to diverse drug-like heterocycles from simple starting materials, but interact or even react with purine bases eventually causing depurination of the DNA tag. To circumvent this impediment to methods development for DELs, we utilize a hexathymidine sequence “hexT” as an adapter oligonucleotide in the initial step of DEL synthesis (Figure 1).[3] The hexT tolerated several catalysts and harsh reaction conditions for target heterocycle synthesis that are usually not reconcilable with DNA. The hexT-heterocycle conjugates were readily ligated to coding DNA sequences with a hexa-adenosine overhang.

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1:05
Lunch Provided by GTCbio for All Attendees || Lunch with Mentors (RSVP only)
Novel Computational Methods & Predictive Models
Moderator: Anna K. H. Hirsch, Helmholtz Institute for Pharmaceutical Research Saarland
2:30
Rationalizing the Membrane Permeability of Cyclic Peptides
 
Sereina  Riniker
Sereina Riniker
Professor, Physical Chemistry
ETH Zurich
About Speaker: Sereina Riniker has been an Assistant Professor (with tenure track) of Computational Chemistry at the Laboratory of Physical Chemistry since June 2014. She was born in Switzerland in 1985. In 2008, she completed her master’s degree in chemistry a... Read Full Bio 
 
 
Sereina Riniker
Professor, Physical Chemistry
ETH Zurich
 
About Speaker:

Sereina Riniker has been an Assistant Professor (with tenure track) of Computational Chemistry at the Laboratory of Physical Chemistry since June 2014.

She was born in Switzerland in 1985.

In 2008, she completed her master’s degree in chemistry at ETH Zurich, with a research project at the Autonomous University of Barcelona with Prof. Xavier Daura. After an internship in the research department of Givaudan AG and a research stay in the group of Prof. Berend Smit at UC Berkeley, she returned in 2009 to ETH Zurich to obtain a PhD in molecular dynamics simulations with Prof. Wilfred van Gunsteren.

From 2012 to 2014, she held a postdoctoral position in cheminformatics under the supervision of Dr. Gregory Landrum at the Novartis Institutes for BioMedical Research in Basel and Cambridge, Massachusetts.

 
Abstract: The hypothesis for the passive membrane permeability of cyclic peptides involves the interconversion between open conformations (with the backbone ...Read More 

The hypothesis for the passive membrane permeability of cyclic peptides involves the interconversion between open conformations (with the backbone amides positioned for hydrogen bonds with the solvent), and closed conformations (with intramolecular backbone hydrogen bonds) prior to the entering of the membrane. Kinetic models based on multi-microsecond molecular dynamics (MD) simulations of the natural product cyclosporine A and its synthetic derivative cyclosporine E in polar and apolar environments reveal that, although similar open and closed conformational states exist, the interconversion rates between them differ substantially for the two peptides. Furthermore, an additional half-opened congruent state was observed for cyclosporine A, which was not present with cyclosporine E. These observations offer a rational for the difference in membrane permeability between cyclosporine A and E by one order of magnitude. These findings are supported by the good qualitative agreement between the kinetic models and the experimental NMR data. The workflow is further applied to a recently published series of cyclic decapeptides, which a backbone skeleton specifically designed for inherent passive membrane permeability. These structurally closely related peptides exhibit different degrees of permeability and solubility. Using our kinetic models, a rational for the observed differences is provided.

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2:55
Performance of Conformal Prediction in Prospective Applications of QSAR and QSPR Models Supporting Drug Discovery
 
Ingo  Mugge
Ingo Mugge
Senior Research Fellow
Alkermes
About Speaker: Dr. Ingo Mügge is a Senior Research Fellow at Alkermes, Inc. In this role he leads the Modeling & Informatics efforts in the Discovery department contributing to the advancement of early drug discovery projects. Dr. Mügge has more than 20 years... Read Full Bio 
 
 
Ingo Mugge
Senior Research Fellow
Alkermes
 
About Speaker:

Dr. Ingo Mügge is a Senior Research Fellow at Alkermes, Inc. In this role he leads the Modeling & Informatics efforts in the Discovery department contributing to the advancement of early drug discovery projects. Dr. Mügge has more than 20 years of experience working in the pharmaceutical industry in leadership positions at Bayer Healthcare, Boehringer Ingelheim, and Alkermes focusing on research in CNS, immunology, and cardio-metabolic related diseases. His research interests include in silico driven drug design techniques such as virtual screening, structure-based drug design, and predictive modeling. He has published more than 60 scientific papers and book chapters, co-organized scientific conferences, and serves on the scientific advisory board of Molecular Informatics. Dr. Mügge holds a European diploma degree in physics from the Humboldt University Berlin and a doctorate degree in computational chemistry from the Free University Berlin. Postdoctoral appointments allowed him to work with Yvonne Martin at Abbott Laboratories and Arieh Warshel at the University of Southern California.

 
Abstract: Decisions made by drug design teams on synthesizing and advancing compounds for lead optimization are increasingly influenced by in silico predicti...Read More 

Decisions made by drug design teams on synthesizing and advancing compounds for lead optimization are increasingly influenced by in silico predictions of on- and off-target activities as well as physico-chemical and ADME properties of small molecules. Predictive modeling workflows involving multiple endpoints are put in place helping chemists to make early decisions on the fate of design ideas or compound advancement. Therefore, it is of paramount importance to assess quantitatively the confidence in each prediction. In analogy to weather predictions, an intuitive measure of the confidence in a prediction is the percent chance to be correct within a certain activity or property range. To this end, the conformal prediction (CP) formalism was employed providing a well-defined mathematical framework for confidence assessments [1]. It was demonstrated before that CP generates efficient and accurate confidence intervals for self-contained data sets [2]. Here we show how CP performs for quasi-prospective (time-split) and also truly prospective predictions. In addition, we show how public data available from Chembl or PubChem perform in predicting compound properties and ADME parameters for compounds measured in related but not identical assays for end points such as aqueous solubility, volume of distribution, and plasma protein binding. For a series of automatically updating models in comparison to static models frozen in time we show that the conformal prediction approach performs robustly in both cases. The observed deterioration in the predictive power of static models over time [3] leads to larger confidence intervals. While the prediction accuracy is maintained static models become less useful over time because of the increasing confidence intervals. The data suggest that CP provides a practical and robust framework for assessing the predictive power of predictive models for prospective applications.

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3:20
Exploring Protein-Ligand Binding Using Three-Dimensional Pharmacophore Patterns
 
Gerhard  Wolber
Gerhard Wolber
Professor
Freie Universität Berlin
About Speaker: Prof. Dr. Gerhard Wolber is professor for Pharmaceutical Chemistry and head of the molecular design lab at the Institute of Pharmacy at the Freie Universitaet Berlin. After his studies of pharmacy at the University of Innsbruck and Computer Science a... Read Full Bio 
 
 
Gerhard Wolber
Professor
Freie Universität Berlin
 
About Speaker:

Prof. Dr. Gerhard Wolber is professor for Pharmaceutical Chemistry and head of the molecular design lab at the Institute of Pharmacy at the Freie Universitaet Berlin. After his studies of pharmacy at the University of Innsbruck and Computer Science at the Technical University of Vienna, he received his PhD in pharmaceutical chemistry at the University of Innsbruck. In 2003 he co-founded the company Inte:Ligand together with partners from the University of Innsbruck, Austria. In 2008 he changed back to academia as assistant professor and group head of the Computer-Aided drug design group at the University of Innsbruck before changing to the Freie Universitaet Berlin in 2010. His research focuses on computational drug design and the development of drug development and virtual screening tools.

 
Abstract: 3D pharmacophores have become an established and consolidated method for in-silico drug discovery – mainly due to their ability to reflect th...Read More 

3D pharmacophores have become an established and consolidated method for in-silico drug discovery – mainly due to their ability to reflect the way of thinking of medicinal chemists in terms of hit identification, hit expansion and lead optimization. The simplicity and descriptive character of such a 3D pharmacophore model thus enables clear communication and rapid feedback cycles between modeling and synthesis teams. Despite the broad usage of the methodology, there are still several pitfalls and challenges for successful pharmacophore modeling – mainly related to the algorithmic challenge of flexibly fitting a molecule to a 3D pharmacophore model in a computationally efficient way. In this talk, structure- and ligand-based 3D pharmacophore application studies will be presented and critically discussed in the context of virtual screening algorithms and overlay algorithms.

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3:45
Towards the Next Generation of FEP Calculations in Lead Compound Optimization
 
Thomas Steinbrecher
Thomas Steinbrecher
Regional Manager, Application Science
Schrödinger
About Speaker: Thomas Steinbrecher studied Chemistry at the University of Freiburg in Germany and earned a diploma with distinction in Physical Chemistry. He completed a Ph.D. thesis on “Computer Simulations of Protein-Ligand Interactions” in 2005. He joined th... Read Full Bio 
 
 
Thomas Steinbrecher
Regional Manager, Application Science
Schrödinger
 
About Speaker:

Thomas Steinbrecher studied Chemistry at the University of Freiburg in Germany and earned a diploma with distinction in Physical Chemistry. He completed a Ph.D. thesis on “Computer Simulations of Protein-Ligand Interactions” in 2005. He joined the developer team of the Amber MD package as a Postdoc at the Scripps Research Institute in San Diego and Rutgers University in New Jersey. The work focus was on efficient free energy calculation methods and QM/MM simulations of charge transfer. After returning to Germany in 2008, Thomas established a junior research group at the Karlsruhe Institute of Technology, working on fast electron transfer phenomena in DNA and proteins. He joined Schrodinger in 2013 where he is responsible for the large scale application of free energy calculation methods in pharmaceutical drug design. He currently is responsible for the European Applications Science Department.

 
Abstract: The accurate prediction of protein−ligand binding affinities, famously described as the holy grail of molecular modelling, represents an extr...Read More 

The accurate prediction of protein−ligand binding affinities, famously described as the holy grail of molecular modelling, represents an extraordinarily challenging task, but also a potential high-value application of computer-aided drug design in the pharmaceutical industry.

Free energy perturbation (FEP) calculations using molecular dynamics simulation (MD) sampling is by far the most widely employed approach to achieve accurate binding free energy predictions. The FEP+ methodology is based on a rigorous statistical mechanics framework, a robust, physics-based representation of the system energetics, and explicit treatment of the important degrees of freedom in the system, including explicit water molecules and full ligand and receptor flexibility. We have in the past reported on many advances in free energy methods, among them employing enhanced sampling methods, building state-of-the-art force fields, and automatic generation of molecule transformation networks.

In this talk, we outline recent advances towards next-generation FEP+ applications, both for increasing simulation throughput as well as broadening the technology’s domain of applicability. The focus will be on current hot topics in pharmaceutical research, such as applying FEP+ calculations to macrocycles, covalent inhibitors or scaffold core-hopping. Together with the continuing vast increase in computational resources due to GPU and cloud computing, this progress has made FEP+ a viable and robust technology to drive hit-to-lead and lead optimization, allowing for the exploration of chemical space in silico with unprecedented accuracy.

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4:10
Afternoon Networking Break
Novel Computational Methods & Predictive Models (cont.)
Moderator: Thomas Steinbrecher, Schrödinger
4:40
Protein Dynamics and Drug Discovery: New Activators of the Hsp90 Chaperone as Anticancer Molecules
 
Giorgio  Colombo
Giorgio Colombo
Principal Investigator
Istituto di Chimica del Riconoscimento Molecolare, CNR
About Speaker: Giorgio Colombo (born 24th June 1971) received his M.Sc. Degree in chemistry in the academic year 1994/1995 from the University of Milano, Final Grade 110/110. After that, he continued his studies obtaining a Ph.D. in chemical sciences from the Unive... Read Full Bio 
 
 
Giorgio Colombo
Principal Investigator
Istituto di Chimica del Riconoscimento Molecolare, CNR
 
About Speaker:

Giorgio Colombo (born 24th June 1971) received his M.Sc. Degree in chemistry in the academic year 1994/1995 from the University of Milano, Final Grade 110/110. After that, he continued his studies obtaining a Ph.D. in chemical sciences from the University of Milano in 2000. During the Ph.D period he spent one year as a visiting scientist in the laboratory of Prof. Ken Merz at the Pennsylvania State University, working on computational and theoretical approaches to study enzymatic and protein properties. He then moved to the University of Groningen as a postdoctoral fellow to work on the molecular dynamics simulations of the folding and stability of proteins and peptides. Dr. Giorgio Colombo joined the Institute for Molecular Recognition Chemistry, Italian National Research Council, in 2001 where he is currently head of the biocomputing group. In 2017, he has been appointed as a Full Professor of Organic Chemistry at the University of Pavia. He is author or coauthor of more than 150 scientific publications, all on international journals.

 
Abstract: Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and ...Read More 

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through the computational design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 Å from the active site.

Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules’ effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary.

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5:05
Getting the Most out of Protein Structures: Structure-Based Molecular Design in the Big Data Era
 
Matthias  Rarey
Matthias Rarey
Professor, ZBH Center for Bioinformatics
Universität Hamburg
About Speaker: Prof. Dr. Matthias Rarey heads the Center for Bioinformatics at the University of Hamburg, Germany.His background is in Computer Science (M.Sc. Paderborn, 1992, Ph.D. Bonn, 1996) with a focus on Bio- and Cheminformatics. Until July 2002, he was group... Read Full Bio 
 
 
Matthias Rarey
Professor, ZBH Center for Bioinformatics
Universität Hamburg
 
About Speaker:

Prof. Dr. Matthias Rarey heads the Center for Bioinformatics at the University of Hamburg, Germany.His background is in Computer Science (M.Sc. Paderborn, 1992, Ph.D. Bonn, 1996) with a focus on Bio- and Cheminformatics. Until July 2002, he was group leader for Cheminformatics at the Fraunhofer Institute for Algorithms and Scientific Computing (SCAI, former part of GMD). In 1997 and 2000, Prof. Rarey performed research in the cheminformatics departments of SmithKline Beecham (King of Prussia, PA) and Roche Bioscience (Palo Alto, CA). Prof. Rarey is a co-founder of the cheminformatics company BioSolveIT GmbH located in Sankt Augustin. Since 2002, he heads the Center for Bioinformatics at the University of Hamburg. He is the director of the Research Group for Computational Molecular Design which focuses on the development of new algorithms for problems occurring in molecular design, innovative approaches to cheminformatics and new molecular visualization techniques. Since 1993, Prof. Dr. Matthias Rarey has been developing innovative Software tools for structure- and ligand-based molecular design, several of which have gained international recognition, e.g. FlexX, Features Trees, PoseView, SMARTSeditor, Mona, ProToss and HYDE.

Since 2014, Prof. Rarey is an Associate Editor of the Journal of Chemical Information and Modeling of the American Chemical Society. Furthermore, he is a member in the scientific committees of Wire Computational Molecular Science and the Journal of Molecular Graphics and Modelling as well as several national and international conferences program committees. He is the spokesman of the Fachgruppe Bioinformatik (FaBI), a joint working group founded in 2014 by the Gesellschaft für Informatik e.V., the Dechema e.V., the Gesellschaft für Biochemie und Molekularchemie and the Gesellschaft Deutscher Chemiker (GDCh).

Together with his colleagues, Prof. Rarey established the study programs M.Sc. Bioinformatik and B.Sc. Computing in Science and is a member of their examinations boards as well as the responsible for the study program M.Sc. Bioinformatik. Prof. Rarey is a member of the faculty council of the Faculty of Mathematics, Informatics and Natural Sciences, he heads the PhD committee of the Faculty of Informatics. He is a liaison professor for the Studienstiftung des deutschen Volkes.

 
Abstract: With the availability of more and more protein structures, structure-based design became a key technology within the early phases of drug design. P...Read More 

With the availability of more and more protein structures, structure-based design became a key technology within the early phases of drug design. Protein structures are the only mean by which a truly rational design approach get in sight. While modeling techniques like docking and scoring dealing with small series of protein structures are well established, our methodologies to explore the wealth of information hidden in large collections of protein structures are still rather limited. Most search engines on protein structures are based on text rather than on structural elements and the analysis of protein structure still requires labor-intense manual steps.

In this talk, new technologies will be presented addressing this opportunity to learn from large structure collections [1,2]. On the one hand, the automation of structure preprocessing in the context of drug design play a crucial role in exploiting large amount of structural data. On the other hand, search methods allowing to perform geometric queries to structures enable knowledge-driven design decisions. Several examples ranging from interaction geometry analysis, molecular flexibility analysis to design by analogy will be presented.

[1] Fährrolfes, R.; Bietz, S.; Flachsenberg, F.; Meyder, A.; Nittinger, E.; Otto, T.; Volkamer, A.; Rarey, M. (2017). ProteinsPlus: a web portal for structure analysis of macromolecules. Nucleic Acids Research, 45:W337-W343.
[2] Bietz, S.; Inhester, T.; Lauck, F.; Sommer, K.; von Behren, M.; Fährrolfes, R.; Flachsenberg, F.; Meyder, A.; Nittinger, E.; Otto, T.; Hilbig, M.; Schomburg, K.; Volkamer, A.; Rarey, M. (2017). From cheminformatics to structure-based design: Web services and desktop applications based on the NAOMI library. Journal of Biotechnology:in press.

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5:30
Structure-Based Computational Methods for Kinase-Centric Drug Development
 
Andrea  Volkamer
Andrea Volkamer
Assistant Professor, Physiology
Charité Universitätsmedizin Berlin
About Speaker: Andrea Volkamer received her Master degree in Bioinformatics from Saarland University in 2007. After a one year research stay at Purdue University (USA), she joint the group of Prof. Dr. M. Rarey at the ZBH, Hamburg. In 2013, she defended her PhD the... Read Full Bio 
 
 
Andrea Volkamer
Assistant Professor, Physiology
Charité Universitätsmedizin Berlin
 
About Speaker:

Andrea Volkamer received her Master degree in Bioinformatics from Saarland University in 2007. After a one year research stay at Purdue University (USA), she joint the group of Prof. Dr. M. Rarey at the ZBH, Hamburg. In 2013, she defended her PhD thesis with focus on computational active site and druggability predictions. After a short ProExzellezia PostDoc period, she joint BioMedX Innovation Center in Heidelberg as a PostDoc researcher, where she has been working on tools to assist the development of selective kinase inhibitors. Since July 2016, Andrea Volkamer has been an assistant professor at the Charité Berlin with the focus on structural bioinformatics and in-silico toxicicology predictions.

 
Abstract: Protein kinases are involved in a variety of diseases including cancer, inflammation, and autoimmune disorders. The focus of pharmaceutical researc...Read More 

Protein kinases are involved in a variety of diseases including cancer, inflammation, and autoimmune disorders. The focus of pharmaceutical research on this enzyme class resulted in roughly 34 FDA approved small molecules. Nevertheless, only a small number of kinases are established therapeutic key targets and most kinase inhibitors are unintentionally promiscuous [1].

Over the last years, several computational methods have been developed to address these shortcomings in kinase-centric drug development. An extract of such will be showcased here. First, using the wealth of available kinase structures, a computational druggability assessment of the entire human kinome will be presented which allows prioritizing (yet) untapped kinases for drug discovery efforts [2]. Second, a novel structure-based approach to tackle compound selectivity deficits will be introduced [3]. The method allows identifying specificity-determining subpockets between closely related kinases, i.e., key- and off-targets, solely based on their three-dimensional structures. Finally, current attempts for structure-based off-target identification will be discussed.

The methods incorporate the wealth of available structural information and can be applied (I) to prioritize novel kinases as drug targets, (II) to detect similarities and dissimilarities between hundreds of structures at once as well as (III) to identify potential off-targets, and, thus, can facilitate the design of more selective compounds.

References:
[1] Kooistra A., Volkamer A., “Kinase-Centric Computational Drug Development”, in Annual Reports in Medicinal Chemistry, Vol. 50, ed. Goodnow R., Elsevier, 2017, 153-192, in press
[2] Volkamer A., Eid S., Turk S., Jaeger S., Rippmann F., Fulle S., ”Pocketome of human kinases: Prioritizing the ATP binding sites of (yet) untapped protein kinases for drug discovery”. JCIM, 2015, 55(3):538-49
[3] Volkamer A., Eid S., Turk S., Rippmann F., Fulle S., “Identification and Visualization of Kinase-Specific Subpockets”, JCIM, 2016, 56(2):335-46

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5:55
Identification of Potent Inhibitors of the Anti-Infective Target DXS using Ligand-Based Virtual Screening
 
Anna Hirsch
Anna K. H. Hirsch
Professor, Drug Design and Optimization
Helmholtz Institute for Pharmaceutical Research Saarland
About Speaker: Anna Hirsch read Natural Sciences with a focus on Chemistry at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology, doing a research project with Prof. Timothy Jamison on the total synthesis of amphidinol... Read Full Bio 
 
 
Anna K. H. Hirsch
Professor, Drug Design and Optimization
Helmholtz Institute for Pharmaceutical Research Saarland
 
About Speaker:

Anna Hirsch read Natural Sciences with a focus on Chemistry at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology, doing a research project with Prof. Timothy Jamison on the total synthesis of amphidinolide T1.

For her Master’s project, she returned to Cambridge to develop the double conjugate addition of dithiols to propargylic carbonyl systems reaction in the group of Prof. Steven V. Ley.

She received her Ph.D. from the ETH Zurich in 2008. Her research was carried out in the group of Prof. François Diederich and consisted of de novo structure-based design and the synthesis of the first inhibitors for an enzyme as a novel approach to treat malaria.

Subsequently, she joined the group of Prof. Jean-Marie Lehn at the Institut de Science et d’Ingénierie Supramoléculaires (ISIS) in Strasbourg, before taking up a position as assistant professor at the Stratingh Institute for Chemistry at the University of Groningen in 2010. In 2015, she was promoted to associate professor of structure-based drug design. 

In 2017, she moved to the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), where she heads the department for drug design and optimization. Her work focuses on rational approaches to drug design (with a strong focus on anti-infective targets), including structure- and fragment-based drug design in combination with dynamic combinatorial chemistry and kinetic target-guided synthesis. 

Anna Hirsch was awarded the Gratama Science Prize in 2014, the SCT-Servier Prize for Medicinal Chemistry in 2015 and the Innovation Prize for Medicinal Chemistry of the GdCh/DPhG in 2017. 

 
Abstract: The enzymes of the methylerythritol phosphate (MEP) pathway are important drug targets given that pathogens such as Mycobacterium tuberculosis and ...Read More 

The enzymes of the methylerythritol phosphate (MEP) pathway are important drug targets given that pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum use this pathway for the biosynthesis of the essential isoprenoid precursors isopentenyl dipohsphate (IPP) and dimethylallyl diphosphate (DMAPP), while humans exclusively utilise an alternative pathway.[1] The thiamine-diphosphate-dependent enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXS) catalyses the first and rate-limiting step of the MEP pathway.

To expand the structural diversity and obtain potent and selective inhibitors of DXS, we performed a ligand-based virtual screening (LBVS) campaign based on shape similarity to screen the ZINC database, starting from previsouly discovered DXS inhibitors as references.[2,3] Biochemical evaluation of the top-scoring compounds against M. tuberculosis DXS and further rounds of LBVS using the best hits as references afforded inhibitors in the single-digit micromolar range. In addition to the promising biochemical activity, the hits are active in cell-based assays against P. falciparum and even drug-resistant strains of M. tuberculosis. Further assays demonstrated their selectivity over mammalian thiamine-diphosphate-dependent enzymes, their lack of cytotoxicity and validated DXS as the intracellular target.[4]

References:
1. Masini T, Hirsch AKH, J. Med. Chem. 2014, 57, 9740–9763.
2. Reymond J-L, Awale M, ACS Chem. Neurosci. 2012, 3, 649–657.
3. Masini T, Pilger J, Kroezen BS, Illarionov B, Lottmann P, Fischer M, Griesinger C, Hirsch AKH, Chem. Sci. 2014, 5, 3543–3551.
4. Hirsch AKH, Reymond J-L, Masini T, Simonin C. EP15160746.2. Manuscript in preparation.

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6:20
Networking Reception & Poster Session
Day - 4 Friday, November 17th, 2017
8:00
Breakfast at Restaurant (included for those staying at the Radisson Blu)
Epigenetic Based Inhibitors
Moderator: Sharad Verma, Johns Hopkins University School of Medicine
9:00
The Design and Optimization of Orally Bioavailable EZH2 Inhibitors
 
Steven  Knight
Steven Knight
Scientific Leader, Cancer Epigenetics Discovery Performance Unit
GSK
About Speaker: Dr. Steven Knight is a Scientific Leader at GlaxoSmithKline. His career has spanned over 21 years at GSK, where he has led multiple program teams to deliver clinical candidates, including inhibitors of the PI3K pathway and mitotic kinesins. Dr. Knigh... Read Full Bio 
 
 
Steven Knight
Scientific Leader, Cancer Epigenetics Discovery Performance Unit
GSK
 
About Speaker:

Dr. Steven Knight is a Scientific Leader at GlaxoSmithKline. His career has spanned over 21 years at GSK, where he has led multiple program teams to deliver clinical candidates, including inhibitors of the PI3K pathway and mitotic kinesins. Dr. Knight received a B.S. in chemistry from the University of California, Berkeley, a Ph.D. from the University of California, Irvine, and did postdoctoral studies as a NIH fellow at the University of Pennsylvania.

 
Abstract: The Design and Optimization of Orally Bioavailable EZH2 inhibitors The EZH2 histone methyltransferase is frequently mutated in diffuse large B-cell...Read More 

The Design and Optimization of Orally Bioavailable EZH2 inhibitors The EZH2 histone methyltransferase is frequently mutated in diffuse large B-cell lymphoma leading to increased trimethylation of histone H3 lysine 27 (H3K27me3). Drug discovery efforts have previously identified GSK126, a potent and selective inhibitor of EZH2 catalytic activity. GSK126 is currently being evaluated as a clinical oncology agent, however, it requires administration through a central IV port. Through medicinal chemistry optimization, we have developed second generation EZH2 inhibitors with significantly improved potency and physicochemical properties. More importantly, these compounds exhibit excellent in vivo activity following oral administration in mouse xenograft models. Benefits: • Design of compounds with improved developability properties (solubility, etc.) • Using predictive assays to introduce and maximize oral bioavailability • Overcoming selectivity issues • Lead optimization strategy in a fiercely competitive environment

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9:25
Histone Methyltransferases as Therapeutic Targets in Neuroblastoma
 
Karim Malik
Karim Malik
Reader & Associate Professor, Epigenetics, School of Cellular & Molecular Medicine
University of Bristol
About Speaker: Currently, I am a Reader/Associate Professor in Epigenetics, School of Cellular & Molecular Medicine, University of Bristol. My main area of research is paediatric solid tumours, especially neuroblastoma and Wilms’ tumour. My interests include ... Read Full Bio 
 
 
Karim Malik
Reader & Associate Professor, Epigenetics, School of Cellular & Molecular Medicine
University of Bristol
 
About Speaker:

Currently, I am a Reader/Associate Professor in Epigenetics, School of Cellular & Molecular Medicine, University of Bristol. My main area of research is paediatric solid tumours, especially neuroblastoma and Wilms’ tumour. My interests include is histone methyltransferases as potential drug targets and signaling pathways in neuroblastoma. Our work is currently funded by Cancer Research UK, Neuroblastoma UK – Smile with Siddy, the Childrens Cancer and Leukaemia Group and the Biotechnology and Biological Sciences Research Council (BBSRC).

 
Abstract: Neuroblastoma is a very heterogeneous childhood cancer that includes a poor prognosis subset for which new therapeutic agents are urgently required...Read More 

Neuroblastoma is a very heterogeneous childhood cancer that includes a poor prognosis subset for which new therapeutic agents are urgently required. This subset is defined by amplification of the MYCN oncogene. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. However, these mutations occur at low levels and there remains a paucity of druggable oncogenic targets. We therefore investigated the possibility that epigenetic modulators might be key drivers of tumorigenesis in this cancer. Here we report our analysis of these targets, including G9a and PRMT5, as potential druggable entities for novel neuroblastoma therapeutics. We show that, as well as exerting epigenetic effects, histone methyltransferases may have profound influences on neuroblastoma biology via post-translational modification of non-histone proteins, including MYCN. Thus small molecule inhibitors of HMTs may represent promising agents for treatment of high risk neuroblastoma.

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9:50
Selective BET Bromodomain Inhibition as a Potential Antifungal Therapeutic Strategy
 
Jérôme Govin
Jérôme Govin
Independent Team Leader, Biosciences and Biotechnology Institute of Grenoble
University Grenoble Alpes
About Speaker: Dr Govin has been deciphering chromatin signaling pathways in various physiological and pathological contexts. Using model organisms, his work has been revealing molecular mechanisms and inspiring new translational approaches in biomedical research.... Read Full Bio 
 
 
Jérôme Govin
Independent Team Leader, Biosciences and Biotechnology Institute of Grenoble
University Grenoble Alpes
 
About Speaker:

Dr Govin has been deciphering chromatin signaling pathways in various physiological and pathological contexts. Using model organisms, his work has been revealing molecular mechanisms and inspiring new translational approaches in biomedical research.

 
Abstract: Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal ...Read More 

Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. We investigated a chromatin-interacting module, the bromodomain from the BET family of proteins, as a potential antifungal target in pathogenic yeasts. We show that the BET protein Bdf1 is essential in Candida albicans and that mutations inactivating its two bromodomains result in a loss of viability in vitro and decreased virulence in mice. Using high- throughput chemical screening, we identified compounds that inhibit C. albicans Bdf1 in vitro with high selectivity over human bromodomains. Crystal structures of the Bdf1 bromodomains reveal binding modes for these inhibitors that are sterically incompatible with the human BET binding pockets. Furthermore, we identified a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 bromodomain-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

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10:15
Lead Finding for Lysine Methyltransferases – SMYD2 and Beyond
 
Ingo  Hartung
Ingo Hartung
Director, Drug Discovery, Medicinal Chemistry Berlin
Bayer AG
About Speaker: Dr. Ingo Hartung is director for medicinal chemistry at Bayer AG in Berlin and in this role responsible for Bayer’s early research portfolio in the field of immunooncology. Prior to this he lead Bayer’s activities in developing epigenetic probes ... Read Full Bio 
 
 
Ingo Hartung
Director, Drug Discovery, Medicinal Chemistry Berlin
Bayer AG
 
About Speaker:

Dr. Ingo Hartung is director for medicinal chemistry at Bayer AG in Berlin and in this role responsible for Bayer’s early research portfolio in the field of immunooncology. Prior to this he lead Bayer’s activities in developing epigenetic probes in collaboration with the Structural Genomics Consortium. Dr. Hartung joined Bayer (via Schering AG) in 2004 and led optimization projects both in oncology as well as in cardiology. From 2011 to 2015 Dr. Hartung was head of microbiological chemistry at Bayer Healthcare AG. His research interests cover the field of oncology drug discovery, innovation in medicinal chemistry and the use of biocatalysis in life sciences. Dr. Hartung studied chemistry at University of Hannover/Germany and Stanford University/USA and was a postdoctoral fellow in biochemistry at Stanford University. He is a lecturer for medicinal chemistry at the Technical University Berlin/Germany and member of the American Association for Cancer Research (AACR) and the Gesellschaft Deutscher Chemiker (GDCh).

 
Abstract: One in two men and one in three women in the industrialized western world will be diagnosed with cancer in their lifetime. Despite significant adva...Read More 

One in two men and one in three women in the industrialized western world will be diagnosed with cancer in their lifetime. Despite significant advances in the understanding of tumor biology curative treatments or life-extending therapies are urgently needed for the deadliest forms of cancer. Limited reproducibility of published target validation studies has been recognized as one road block for de novo cancer target discovery. The use of unspecific low-quality tool inhibitors for cellular target validation purposes is contributing to this situation. The Structural Genomics Consortium (SGC), a public-private partnership that supports the discovery of new medicines through open access research, addresses this issue by developing high quality small molecular probes for novel targets of interest. Here, I will outline probe discovery challenges and key success factors based on two case studies out of the field of cancer epigenetics.

SMYD2 is a protein methyltransferase which has been described as a regulator of the tumor suppressor p53 and is overexpressed is various solid tumor types. High-throughput screening of three million compounds followed by state-of-the-art hit-to-lead and lead optimization efforts led to the discovery of BAY-598. BAY-598 is a highly selective, cellularly active and orally bioavailable inhibitor of SMYD2. The related lysine methyltransferase SMYD3 was postulated to play a role in MAPK signaling in Ras-mutated tumor cells. Building on key learnings from our SMYD2 inhibitor program, we were able to identify an unprecedented series of SMYD3 inhibitors which was optimized to the potent and selective SMYD3 probe BAY-6035.

I will discuss key success factors and lessons learned from these two projects which have high relevance for lead finding activities within the family of methyltransferases and beyond.

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10:40
Morning Networking Break
Round Table Discussions
Round Table Topics

11:10
1 | Fit for the Future? Current Challenges and Bottlenecks in the Drug Discovery Process
11:10
2 | Machine Learning: Promise or Hype?
12:30
Lunch Provided by GTCbio
2:35
Summit Concludes