RICT 2015
Drug Discovery and Selection

Tjeerd Barf obtained his Ph.D. in Medicinal Chemistry 1996 from the University of Groningen, The Netherlands. He subsequently joined Pharmacia & Upjohn in Uppsala, Sweden, in 1997 and continued his career with the spin-off company Biovitrum (2000). He has led medicinal chemistry programs concerning metabolic diseases and assumed overall program leadership later on. In 2005, he moved to Organon (Oss, The Netherlands), and as a Group Leader, his responsibilities encompassed heading immunology lead finding projects. After the acquisition by Schering-Plough and the merger with Merck, he led a global cross-site lead optimization program in the therapeutic area of autoimmune diseases. The last decade, he has been intimately involved in drug discovery programs that utilize the covalent binding technology, mainly with the focus on covalent kinase inhibitors in the oncology and autoimmune disease space. As of 2011, expansion of these drug discovery activities took place in privately owned biotech companies. He is one of the founders of Acerta Pharma and presently holds the position of EVP of Chemistry.

Current position: Prin. Scientist, Biology-Discovery, Virology & Vaccine Late Discovery Research field: Infectious disease therapeutics Education: Doctor of Philosophy, Cell & Molecular Biology, Pennsylvania State University Candidate for Masters in Pharmaceutical Chemistry University of Florida Bachelor of Science, Biochemistry; Minor in Biology University of Delaware Professional experience: 2007-2014: Idenix Pharmaceuticals, Inc., Director of Biology, HCV Project Team Leader Established and utilized models to investigate the inhibition, resistance and toxicity of small molecules against hepatitis C, among other side projects and responsibilities, including a drug discovery project leader for multiple programs and new target initiatives. 2003-2007: Postdoctoral fellow: Microbiology & Molecular Genetics Harvard Medical School Focused on a genetic system for generation of a recombinant gammaherpesvirus for antiviral assays, vaccine vector candidates for SIV, posttranslational regulation, and microRNA identification. 2002-2003: Postdoctoral fellow: Penn State University Generation and utilization of recombinant insect viruses for gene transfer of mammalian expression cassettes to primary hepatocytes.

Pascal Bonnet is full professor at the Institute of Organic and Analytical Chemistry (ICOA) from the University of Orléans, France, since 2012. He is currently leading the group of Structural Bioinformatics and Chemoinformatics that is developing and integrating novel computational methods in drug discovery. His research interests focus also on the development of an integrative in silico platform for kinase research. After completing his PhD in 2001 at the University of Orléans (France) and the University of Barcelona (Spain), he moved to a postdoctoral position at the University of Manchester, UK. As a scientist, he joined Janssen-Cilag in France and then Janssen-Pharmaceutica, Belgium, in 2003. He was involved in several drug discovery projects mainly in the oncology therapeutic area. Promoted Principal Scientist in 2010, he was leading the Kinase Platform at Janssen including biologists, medicinal and computational chemists.

Paul Brennan received his PhD in organic chemistry from the University of California, Berkeley under the mentorship of Paul Bartlett working on synthetic methodology for combinatorial chemistry and synthesizing inhibitors for new anti-bacterial targets. Following three years of post-doctoral research with Steve Ley in Cambridge University on the total synthesis of rapamycin, Paul returned to California to take a position at Amgen. His research was focussed on designing and synthesizing kinase inhibitors for oncology. After two years at Amgen, Paul accepted a position as medicinal chemistry design lead at the world-renowned Pfizer labs in Sandwich, UK. Over the next six years Paul designed and synthesized compounds for most major drug classes: GPCR’s, CNS-targets, ion-channels and metabolic enzymes. Following the closure of the Pfizer site in Sandwich, Paul joined the Structural Genomics Consortium as the principal investigator for medicinal chemistry to discover chemical probes for epigenetic proteins.

The goal of my research group is to improve understanding of receptor-ligand interactions at the atomic level using computer models. Using structure-based methods such as molecular dynamics simulations and molecular docking, we focus on prediction of how small molecules interact with G protein-coupled receptors and modulate their function. Our projects are driven by computational chemistry and carried out in close collaboration with experimental groups. I completed a PhD in computational chemistry at Uppsala University in 2008 under the supervision of prof. Johan Åqvist. My postdoctoral research was carried out in prof. Brian Shoichet’s group at the University of California in San Francisco and focused on structure-based ligand discovery. In 2012, I established an independent research group at Stockholm University, which currently has eight members. In July 2015, my group will move to the dept. of Organic Pharmaceutical Chemistry and the Science for Life Laboratory at Uppsala University.

JD received his PhD degree in Organic Chemistry in 1996 under the supervision of Prof Meslin at the UFR des Sciences et Techniques in Nantes; he has dedicated this time to the discovery of hetero Diels-Alder reactions to reach novel approaches to a range of heterocycles . In 1997, he joined Professor Young’s group at the University of Sussex as a post-doctoral Fellow, where in worked on the synthesis of unnatural aminoacids containing fluorine and their incorporation into proteins. He joined Vertex in 1998 where he is currently working. JD has been involved in a number of research programmes and has developed leadership responsabilities for kinase projects, mostly in the oncology field. In the past few years, his expertise led him to be appointed as Chemistry Head for the ATR programme, which resulted into the discovery of two clinical candidates, one of which, VX-970, is the topic of today’s presentation.

Dr John Christopher is an Associate Director at Heptares Therapeutics, a clinical-stage biotech focussed on G protein-coupled receptors. He is currently leading projects in the hit-to-lead and lead optimization phases, targeting GPCRs located within the CNS. John has fifteen years experience in the pharmaceutical and biotech industry, having started his career at GSK, Stevenage, in 2000. At GSK he gained valuable experience in the application of fragment-based and structure-based drug discovery techniques to multiple target classes and therapeutic areas, before moving to Heptares in 2010. John was awarded his PhD in synthetic chemistry (supervised by Prof. Philip J. Kocienski FRS) from The University of Glasgow in 2000.

Patrice Courvalin, M.D., is Professor de Classe Exceptionnelle at the Institut Pasteur where he is the Head of the Antibacterial Agents Unit since 1983. He and his collaborators are experts in the genetics and biochemistry of antibiotic resistance. In particular, he first described and then elucidated vancomycin resistance in Enterococcus. His research has led to a revision of the dogma describing natural dissemination of antibiotic resistance genes. He and his colleagues demonstrated that a wide variety of pathogenic bacteria can promiscuously exchange the genetic material conferring antibiotic resistance, proved that conjugation could account for dissemination of resistance determinants between phylogenetically remote bacterial genera, elucidated the transposition mechanism of conjugative transposons from Gram-positive cocci, and more recently, has obtained direct gene and protein transfer from bacteria to mammalian cells. His work is reported in more than 290 publications in international scientific journals.

Dr Rebecca Deprez-Poulain is Professor of Medicinal Chemistry and Industrial Pharmacy at the School of Pharmacy of Lille, France. Her research at INSERM U1177 since 2004, focuses on the inhibition of metalloproteases and on chemical biology strategies to unravel the role of these targets. She holds an engineer degree from HEI and a PharmD. She got her PhD under the supervision of Pr Tartar at CEREP (1999) on combinatorial chemistry and pharmacological profiling. She did a post-doc on chemical libraries for the screening on C elegans in collaboration with DeVGen NV and a second post-doc at UMR8525 for the treatment of malaria. She received the Prix 2009 d’Encouragement à la Recherche de la Société de Chimie Thérapeutique (Servier Prize), is the PI of several national grants (ANR and FRM) and author of more than 40 articles and reviews.

Head Pre-Development Sciences & Head Waltham Site, Lead Generation to Candidate Realization (LGCR), Sanofi. Current responsibilities: Synthesis development, formulation development, and analytical research and development for non-biologics for Sanofi in the US. Prior professional experience: Genzyme in a number of positions including head of discovery chemistry, head of process chemistry, and head of development for non-biologics; Schering-Plough in process research. Education: Boston College B.S. in Chemistry, Brandeis University Ph.D. in Synthetic Organic Chemistry, Massachusetts Institute of Technology Post-Doctoral Associate.

Yuichi Hashimoto received his Ph.D. in pharmaceutical sciences form The University of Tokyo (UTokyo) in 1982. He became an assistant professor of the Faculty of Pharmaceutical Science, UTokyo (1983), then moved to the Institute of Applied Microbiology, UTokyo as an associate professor (1989), and finally joined the Institute of Molecular and Cellular Biosciences, UTokyo as a full professor (1997 to present). His major research interests span the fields of basic molecular medicinal chemistry and bioorganic chemistry, and include studies of the structural development of bioresponse modifiers and regulators of protein trafficking/stability.

Jan Jiricek received his Diploma in Chemistry (1999) at the University of Hannover after completing an undergraduate research year at Scripps in the area of bioorganic chemistry. He graduated at the TU-Berlin in 2003 with summa cum laude in the field of natural product synthesis. After two years of postdoctoral studies at GNF in target based medicinal chemistry, he joined the Novartis Institute for Tropical Diseases with the main focus on TB drug discovery. Through 8 years in this field, Jan became an expert in TB drug discovery where he developed a strong pipeline of lead series and two preclinical development candidates. In his current position, appointed team leader in HAT drug discovery, his responsibility is to develop a world leading drug discovery portfolio for HAT and develop novel urgently needed drugs for this truly neglected disease.

Daniel Meibom received his PhD degree in Organic Chemistry under the supervision of Professor Ekkehard Winterfeldt at the University of Hannover. In 2001 he joined Bayer working on combinatorial chemistry, then quickly moved on to medicinal chemistry projects in therapeutic areas like CNS and antibacterials. From 2007-2013 he was responsible for the chemical optimization of several medicinal chemistry projects in the cardiovascular field. Since 2014 he is heading a cardiovascular lead optimization project as a senior scientist. Besides drug design, his research interests include IT tools for medicinal chemists.

I received an MPhil. in 1999 and a Ph.D. in 2002 both in organic chemistry at the Manchester University, in the UK. During my Ph.D., I was author of 8 publications. I then started my industrial carrier at EvotecOAI, where I developed my expertise in parallel synthesis. Quickly, I joined Faust pharmaceuticals for a new position in 2004, where I did my initiation to medicinal chemistry and neurodegerative diseases, looking for active drugs for mGluRs. I then moved to new challenges at Galapagos. My carrier at Galapagos was paved with successes including the discovery of 7 active small molecules, which moved to preclinical studies. 3 compounds were tested in phase I clinical trial with a positive proof of mechanism in auto-immune diseases. From these 3, 2 are currently in phase II, GLPG0778 and GLPG0634. The two compounds already showed promising results, Psoriasis for GLPG0778 and RA for GLPG0634. GLPG0634 was the first selective JAK1 inhibitor known in clinical trials in inflammatory and auto-immune conditions. I am today leading a group of 25 researchers and I am inventor of more than 16 patents.

Sylviane Muller is a Distinguished class research director in the French Centre National de la Recherche Scientifique (CNRS) and Professor at the Institute of Advanced Studies of the Strasbourg University, in charge of the chair Therapeutic immunology. She is deputy director of the CNRS Molecular and cellular biology Institute (IBMC) in Strasbourg (France), Chair and Director of the CNRS Unit entitled Immunopathology and therapeutic chemistry, and Head and coordinator of the Drug discovery Center for cancer and inflammation Medalis awarded 'Laboratory of Excellence’. She defended a doctoral degree in Molecular Biology in 1978 and a thesis in Science in 1984 in Strasbourg. She was a post-doctoral fellow at the Max-Planck Institute for Immunobiology in Freiburg (Germany). She is the co-author of 249 publications in peer-reviewed journals and 97 review articles and chapters. Her scientific activity has led to ~30 patents (most are licenced). She is the co-founder of two companies, namely Neosystem (1986) and ImmuPharma (2002). She is a member of the editorial board of several scientific journals and of international scientific Societies. She gave numerous lectures in Europe and the US, and participated to many international meetings as an invited speaker. She co-organized ten international congresses in the field of autoimmunity and lupus. She received the CNRS Silver Medal (2009). She is Chevalier de l’Ordre de la Légion d’Honneur (2010).
Research field:
In 2001, S. Muller started her own CNRS laboratory at IBMC, where she concentrates her activity on systemic lupus erythematosus, which represents a prototype of autoimmune rheumatic disease. Pr. Muller’s team is interested in understanding the molecular and cellular pathways involved in autoreactive lymphocytes activation and the events leading to cell death/living phenomena (apoptosis, autophagy) that are central in lupus. Combining fundamental knowledge of lupus with a long-lasting experience in peptide immunochemistry, S. Muller and her team were able to develop a very novel strategy, based on synthetic peptides, designed to modulate the aberrant immune response and restore immune system functions in lupus mice and patients. The results of a peptide-based Phase IIb clinical trial including in ~150 lupus patients gave extremely promising results and a phase III clinical trial has started in 2015.

My name is Sumihiro Nomura. I am a Principal Research Scientist at the Medicinal Chemistry Research Laboratories II of Mitsubishi Tanabe Pharma Corporation, in Saitama, Japan. I am a medicinal chemist with 32 years of experience, leading several drug discovery teams for the treatment of immunological or metabolic disease at Mitsubishi Tanabe. I received my Ph.D. degree from Hokkaido University with a thesis regarding the synthesis of cyclic ether rings found in natural products.

Tudor Oprea completed his medical studies (MD, PhD) in Timisoara, Romania, followed by positions at the University of Utrecht, Washington University School of Medicine and Los Alamos National Laboratory, as well as AstraZeneca R&D in Sweden (1996-2002), where he co-developed the “leadlike” concept and ChemGPS. Since 2002, Oprea joined the University of New Mexico School of Medicine, where he has contributed to the identification of selective, potent compounds for GPER (the G-protein estrogen receptor), the formyl peptide receptors FPR1 and FPR2, the small GTP-ases Rac1 and Cdc42, and the ABCG2 efflux transporter. His work led to clinical trials for Raltegravir (NCT01275183) and Ketorolac (NCT01670799). Oprea co-invented 5 US patents, co-authored over 140 peer-review publications, and received the Corwin Hansch Award. Oprea's research interests include chemical space navigation, lead and probe identification, virtual screening, machine learning, systems chemical biology, signal transduction and pharmacokinetics, drug repurposing and clinical informatics research.

Alleyn Plowright obtained his PhD in organic chemistry with Professor Gerald Pattenden at the University of Nottingham in 1999, and continued with postdoctoral studies with Professor Andrew Myers at Harvard University in 2000–2001. In 2002, he joined AstraZeneca UK as a medicinal chemist working in the Oncology and then Metabolic Disease research areas. He moved to AstraZeneca, Sweden, in 2006 and in 2012 became Senior Principal Scientist, Medicinal Chemistry in the Cardiovascular and Metabolic Diseases Innovative Medicines unit. His research interests include drug design, phenotypic screening and drug discovery for cardiovascular and metabolic diseases.

Dr. Rodriguez was born October 27, 1978 and raised in the south of France by his parents Jean-Paul and Françoise Rodriguez. After receiving his undergraduate degree at the University of Avignon in June 2002, he performed graduate studies at Marseille and Oxford under the supervision of M. Santelli and Sir J. E. Baldwin. During his Ph.D. studies, he completed the total synthesis of several natural products, providing novel chemical ways to create complex molecular frameworks. Following completion of his doctoral studies, he joined the University of Cambridge in November 2005 as a Cancer Research UK postdoctoral fellow under the mentorship of S. Balasubramanian and was promoted to Senior Research Associate in 2009. His research encompassed the design and synthesis of small molecules to study the existence and biological consequence(s) of G-quadruplex nucleic acids in the human genome. In 2012, Raphaël joined the CNRS (ICSN, Gif-sur-Yvette, France) as a group leader and is now based at the Institut Curie Research Centre (Paris). Current research interests include chromatin and cancer stem cell biology.

Michael J. Sofia, Ph.D. is currently CSO of Tekmira/OnCore Inc. a company focused on the discovery and development of therapies to treat HBV. Previously he was CSO and Co-founder of OnCore Biopharma which merged with Tekmira in March 2015. Prior to co-founding OnCore BioPharma, Inc., Mike most recently was Senior Vice President of Chemistry, Princeton Site Head and Senior Advisor at Gilead Sciences. Previously he was Sr. Vice President of Chemistry at Pharmasset, Inc. He joined Pharmasset in 2005 and had responsibility for research strategy, medicinal chemistry, process research, computational chemistry and analytical chemistry functions and was a clinical development project leader. He is an inventor of Sovaldi (sofosbuvir), a treatment of hepatitis C infection currently approved and marketed by Gilead Sciences, Inc. Prior to Pharmasset, he held positions of Group Director, New Leads Chemistry at Bristol-Myers Squibb, Vice President of Research at Intercardia Research Labs (formerly Transcell Technologies) and was Research Investigator and Project Leader at Lilly Research Labs, Eli Lilly & Co. He did his postdoctoral training in synthetic organic chemistry, as an NIH fellow, at Columbia University and earned his Ph.D. in organic chemistry from the University of Illinois, Urbana-Champaign. He received his B.A. degree in chemistry from Cornell University. He has authored 100 publications, 9 book chapters and numerous abstracts and is an inventor on over 30 patents. He also holds a professorship position at the Baruch S. Blumberg Institute and is on the editorial board of several scientific journals. Mike is the recipient of the PA BIO 2014 Scientific Achievement Award for the discovery of Sofosbuvir.

Motonari Uesugi is a Professor of The Institute for Integrated Cell-Material Sciences and Institute for Chemical Research, Kyoto University. After completing postdoctoral training in Harvard Chemistry Department, Dr. Uesugi started his independent career in Baylor College of Medicine, Houston, where he has established an interdisciplinary laboratory in the area of chemical biology. He was tenured in Baylor in 2005, and moved to Kyoto University as a full professor in 2005. He is a recipient of Tokyo Techno Forum 21 Gold Medal Award (2006) and German Innovation Award (2011). Dr. Uesugi and his co-workers aim to gain a fundamental understanding of biological events through the study of small molecules.

John Wai obtained his BSc in chemistry from the University of Hong Kong and his PhD from the University of British Columbia, Canada with late Professor Edward Piers. After finishing his post-doctoral training with Professor K. Barry Sharpless, John joined Merck Research Laboratories, Department of Medicinal Chemistry (West Point, PA) in 1989. At Merck, he contributed to the discovery efforts of a number of programs, from target validation & lead identification to lead optimization & early development. This includes HIV-1 non-nucleoside reverse transcriptase inhibitors, ras-farnesyl protein transferase inhibitors, fibrinogen receptor antagonists, HIV integrase strand transfer inhibitors, HIV RNase H inhibitors, gamma secretase inhibitors, etc. Through the years, John rose through the ranks and was promoted to be Director of Medicinal Chemistry in 2005. In 2007, he received the Distinguished Scientific Award from the inaugural Merck WP Basic Research Reward and Recognition Forum for his work on HIV integrase inhibitors. In 2013, John received the Heroes of Chemistry Award from the American Chemical Society for his contribution to the discovery and development of Isentress, the first HIV integrase inhibitors approved for treatment of AIDS (2007). In 2014, he joined WuXi AppTec (Shanghai) as Vice President of Medicinal Chemistry, and has recently been appointed as Adjunct Professor of Fudan University, College of Pharmacy, Department of Medicinal Chemistry.

Isabel Alves did her undergraduate studies in Portugal and obtained her PhD in Biochemistry from the University of Arizona (Tucson, USA) with Prof. Gordon Tollin and Victor Hruby in 2004. Then she joined the University Pierre et Marie Curie for a post-doctoral fellowship with Dr. Sandrine Sagan where she continued to work with G-protein coupled receptors (GPCRs). In 2006 she obtained a CNRS research position (CR1) to work in the mechanisms of action of membrane active peptides. In 2010 she moved to the CBMN in Bordeaux. She has since then developed a plasmon waveguide resonance (PWR) technique to follow molecular interactions taking place at lipid membranes. More specifically she has been investigating, using PWR and other biophysical approaches, the mechanisms of interaction of membrane active peptides (cell penetrating, viral, antimicrobial, amyloides) and the activation and signaling of GPCRs and role of lipids in these processes.

Frédéric Bihel is currently senior researcher at the French National Center for Scientific Research (CNRS), within the Laboratoire d’Innovation Thérapeutique (UMR7200) at the University of Strasbourg. His research interests are mainly focused on developing chemical tools targeting GPCRs. Prior to join the CNRS in 2005, he got a Ph.D. in organic chemistry (2002) from the University of the Mediterranean (J-L Kraus’ lab, Marseille, France) for his works on the development of isocoumarines as gamma-secretase inhibitors in the Alzheimer’s disease field. In 2003, he moved to the Harvard Medical School and BWH (Boston, MA, USA) in Michael Wolfe’s lab where he designed helical peptides allowing the identification of an initial substrate-binding site of the gamma-secretase, distinct of the active site. Since 2007, a part of his research program is devoted to the development of heterocyclic or peptidic ligands of a GPCR subfamily called the RF-amide receptors (NPFF1 & 2, GPR10, GPR54 and GPR103), and their potential use in pain modulation.

I received PharmD (Doctor of Pharmacy) in 2001 from the Comenius University, Slovakia and PhD in Medicinal Chemistry in 2005 from the University of Bonn, Germany. My post-doctoral fellowship at the Northwestern University, USA (2006-2007) was in molecular pharmacology and preclinical drug development. Currently, I am a Senior Lecturer in Pharmacology and Head of the Molecular Innovations in Kinase Therapeutics laboratory at The University of Sydney, Australia. I have built my program of research around the key themes of medicinal chemistry with a focus on understanding the molecular mechanism of action of kinase inhibitors. In particular, my laboratory has developed novel inhibitors and published on research that focuses on p38 MAPK-MK2, LRRK2 and DYRK1A signalling in neurodegeneration and neuro-oncology.

Christophe Rochais received his PhD with the group of Professor S. Rault from the University of Caen Basse-Normandie (2005). After completing a postdoctoral fellowship at the Centre for Biomolecular Sciences of the University of Nottingham (2007), under the supervision of Professor Peter M. Fischer, he was appointed lecturer in Organic Chemistry in the School of Pharmacy at the University of Caen in 2007. Since January 2014, he has assumed the position of professor in Organic Chemistry. His research interests include medicinal chemistry in the field of enzymatic inhibition, as well as receptor modulation, in order to develop pharmacological tools and bioactive compounds. Since 2012 he has been leading a research program dedicated to the development of pleiotropic agents of interest in the treatment of Alzheimer's disease (PLEIAD).