Advances in Structure-based Drug Design - DOC by Ym19z8Vo

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									                    SINO-AMERICAN BIOMEDICAL & PHARMACEUTICAL PROFESSIONALS ASSOCIATION

                                    Science & Technology Forum X


                                        Frontiers in Oncology

Date:         March 17, 2012 (Saturday) 8:30am To 3:00pm (Lunch will be provided)
Location:     Institute of Americas, UCSD (directions available at www.sabpa.org)
Registration: https://www.123signup.com/register?id=sgrcq
              $20 for online registration, $10 for students and post-docs. $40 for on-site registration,
              Online registration ends March 14, 2012

This year’s SABPA Science & Technology Forum will focus on current frontiers in oncology. The presentations
will address the emerging new trends in cancer drug development including translational research,
pharmacogenetics, personalized targeted therapies, epigenetics, cancer stem cell, oncology clinical design and
development of preclinical models. The meeting will also discuss the opportunities and challenges facing
cancer drug development in San Diego biotech and pharmaceutical community:                 industry/academic
collaboration; cancer clinical trials and venture funding in San Diego.

This forum has brought together leaders in academic and industry in the oncology field to ignite the exchange of
ideas of how to build a stronger oncology community in San Diego.



SPEAKERS

David Cheresh, Ph.D.
Professor of Pathology, Associate Director for Translation Research, Moores UCSD Cancer Center

Greg Reyes, M.D., Ph.D.
Senior Vice President, Drug Discovery, Celgene

Isan Chen, M.D.
Chief Medical Officer, Aragon

Jean Cui, Ph.D.
Associate research fellow, Pfizer

Jeremy Barton, M.D.
Vice President Precision Medicine, Pfizer

Jing Yang, Ph.D.
Assistant Professor of Pharmacology and Pediatrics, UCSD

Laure Escoubert-Lozach, Ph.D.
Senior Scientist, Celgene

Steve Kaldor, Ph.D.
Venture Partner at Versant Ventures, acting CEO, QuantiCel

Tannishtha Reya, Ph.D.
Professor, Department of Pharmacology, UCSD
       www.SABPA.org | Science & Technology Forum X




                                                 Program

8:30-9:00     Registration & Breakfast
9:00-9:05     Opening Remarks: Yi Liu, Ph.D., VP of drug discovery, Intellikine
              Chairperson of session 1: Hua Gong, Ph.D., Executive Director of Medical Diagnostics
9:05-9:10
              Premier Research Group
              David Cheresh, Ph.D.
              Professor of Pathology, Associate Director for Translation Research, Moores UCSD Cancer
9:10-9:40
              Center
              Title: A MEK-independent role for CRAF in mitosis, angiogenesis and tumor progression
              Abstract: RAF kinases regulate cell proliferation and survival and can be mutated or
              dysregulated in tumors. A role for RAF in cell proliferation has been linked to its ability to
              activate MEK/ERK. Here, we identify a MEK-independent role for RAF in tumor growth.
              Specifically, in mitotic tumor and endothelial cells, CRAF becomes highly phosphorylated on
              serine 338 and localizes to the mitotic spindle poles from pro-metaphase until anaphase.
              Treatment of tumor and endothelial cells with allosteric, but not ATP-competitive RAF inhibitors
              prevents CRAF phosphorylation on serine 338, localization to the mitotic spindle and causes cell
              cycle arrest at pro-metaphase. Furthermore, we identify phospho-S338 CRAF as a potential
              biomarker for tumor progression, aberrant vascular proliferation and a surrogate marker for
              allosteric RAF blockade. Mechanistically, CRAF, but not BRAF is found in a complex with Polo-
              like kinase 1 at the centrosomes/spindle poles during G2/Mitosis. Indeed, allosteric or genetic
              inhibition of phospho-S338 CRAF impairs Plk1 activity and its accumulation at kinetochores
              causing pro-metaphase arrest, while a phospho-mimetic S338D CRAF mutant potentiates Plk1
              activation, mitosis, angiogenesis and tumor progression in mice. These findings reveal a
              previously undefined role for RAF in angiogenesis and tumor progression beyond the RAF-MEK-
              ERK paradigm, opening new avenues for targeting RAF in oncology.
              Laure Escoubert-Lozach, Ph.D.
9:40-10:10    Senior Scientist, Celgene
              Title: Epigenetics and Cancer
              Abstract: At Celgene Corporation, we are engaged in the discovery, development and
              commercialization of novel therapies for the treatment of cancer and inflammatory diseases
              through gene and protein regulation and we believe that epigenetic therapy represents a
              promising avenue for targeting these diseases.
              Azacitidine (Vidaza®) is the first approved drug that works via an epigenetic mechanism.
              Vidaza®, approved for the treatment of Myelodysplastic Syndromes, is believed to exert
              antineoplastic effects by causing DNA hypomethylation and direct cytotoxicity on abnormal
              hematopoietic cells in the bone marrow. Celgene also markets the HDAC inhibitor Romidepsin
              (Istodax®), which is approved in the United States for the treatment of cutaneous T-cell
              lymphoma and peripheral T-cell lymphoma. In addition, Celgene’s immunomodulatory
              compounds have been described to modify gene expression through epigenetic mechanisms.
              We are now investigating novel epigenetic targets and during this seminar, our strategy for the
              identification and validation of new epigenetic drugs for oncology and our effort to target cancer
              stem cells will be presented.
              We believe that our growing investment in the development of epigenetic agents will allow us to
              provide physicians/clinicians with more solutions for managing complex human disorders such
              as cancer and inflammatory diseases.
              Jean Cui, Ph.D.
10:10-10:40   Associate research fellow, Pfizer
              Title: Invention of Xalkori (Crizotinib): from a Kinase Inhibitor to a Drug
              Abstract: Crizotinib, a potent c-Met/ALK dual inhibitor, was fast track approved in August 26,
              2011 by FDA for late stage lung cancer patients with EML4-ALK fusion gene based on marked
              efficacy results from Phase I and II studies. The invention of crizotinib starts from a cocrystal
              structure of c-Met/PHA-665752 complex. The cocrystal structure of PHA-665752, bound to c-
              MET kinase domain, revealed a novel ATP site environment, which served as the target to guide
       www.SABPA.org | Science & Technology Forum X
              parallel, multi-attribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was
              created to more effectively make the key interactions achieved with PHA-665752. In the novel
              series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as
              the 2,6-dichlorophenyl group of PHA-665752 via a more direct vector, and thus with a better
              ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate
              crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK
              inhibition, effective tumor growth inhibition, and good pharmaceutical properties and safety
              profile.
10:40-11:00   Refreshment Break, Exhibit & Networking
11:00-11:05   Chairperson of session 2: Wen Luo Ph.D., CSO, Denovo Biomarkers
              Steve Kaldor, Ph.D.
              Venture Partner at Versant Ventures, acting CEO, QuantiCel
11:05-11:35
              Title: Creating Science and Business Value in San Diego Biotech: Case Studies and Possible
              Strategies for Future Success
              Abstract: In the last 20 plus years, I’ve had the opportunity to participate in the growth of the
              San Diego biotech industry through my involvement in multiple innovative drug discovery
              companies, a number of which have produced both marketed drugs and high value liquidity
              events for investors. In this talk, I’ll highlight several of these companies plus my current work
              with Quanticel and Versant Ventures. The goal of this talk will be to provide the audience with
              insights into what has worked, and what is likely to work going forward in creating successful
              biotech companies which emphasize Research and early phase Development. I’ll also offer
              some tailored comments on oncology-focused biotechs.
              Jing Yang, Ph.D.
11:35-12:05   Assistant professor of pharmacology and pediatrics, UCSD
              Title: Exploring a New Twist on Tumor Metastasis
              Abstract: Tumor cells acquire the ability to degrade basement membrane and extracellular
              matrix (ECM) in order to invade and metastasize to distant organs. The molecular triggers for
              matrix degradation in tumor cells are largely unknown. The Twist1 transcription factor plays key
              roles in tumor metastasis and is known to induce Epithelial-Mesenchymal Transition (EMT).
              Here we report a novel function of Twist1 in promoting extracellular matrix degradation by
              inducing the formation of invadopodia.
              Invadopodia are specialized actin-based membrane protrusions that degrade ECM via clustering
              of proteases. Twist1 induces PDGFRα expression, which in turn activates Src kinase in various
              breast tumor cells. Phosphorylation of multiple invadopodia components by Src kinase promotes
              invadopodia assembly and matrix degradation. We show that Twist1 and PDGFRα are central
              mediators of invadopodia formation and ECM degradation in response to various EMT-inducing
              signals, including TGFβ and Snail1. Induction of PDGFRα and invadopodia is essential for the
              ability of Twist1 to promote invadopodia formation, local tumor invasion, and distant metastasis
              in vivo. Consistent with PDGFRα being a direct transcriptional target of Twist1, expression of
              Twist1 and PDGFRα is highly correlated and associated with poor survival in breast cancer
              patients. Together, our study demonstrates that invadopodia-mediated matrix degradation is a
              key function of
              Twist1 in promoting tumor metastasis. Furthermore, it reveals that matrix degradation and loss of
              cell adhesion are regulated by different EMT-inducing transcription factors. This explains why
              multiple factors need to be activated coordinately to promote carcinoma cells to undergo EMT
              and invade. We also identify PDGFRα as a direct transcriptional target of Twist1 in promoting
              invadopodia formation and tumor metastasis, therefore suggesting that PDGFRs might be
              potential targets for anti-metastasis therapies.
12:05-1:00    Lunch
              Chairperson of session 3: Marie Zhang, Ph.D. MBA, Co-Founder and COO of MicroStem,
1:00-1:05
              Inc.
              Isan Chen, M.D.
1:05-1:35     Chief Medical Officer, Aragon
              Title: Challenges and Opportunities in Oncology Drug Development
              Abstract: Drug development is a high-risk industry and the field of oncology clinical
              development is specially challenging. Present clinical development paradigm is not sustainable
              in the long term. Close collaboration to remove unnecessary barriers among industry, and
              between industry and academia is necessary. Understanding the regulatory environment and the
       www.SABPA.org | Science & Technology Forum X
            disease landscape are critical.
            An example of the challenges facing drug development in prostate cancer is presented.
            Tannishtha Reya, Ph.D
1:35-2:05   Professor, Department of Pharmacology, UCSD
            Title: Understanding the Dynamics of Cancer: from Developmental Pathways to in vivo Imaging
            Abstract: Our research focuses on the signals that control hematopoietic stem cell self-renewal
            and differentiation, how these signals are utilized during regeneration and how their
            dysregulation may lead to cancer. Using a multitude of genetic models, we have shown that
            classic developmental signaling pathways such as Wnt, Hedgehog and Notch play key roles in
            stem cell growth and regeneration and are dysregulated during leukemia development. In
            addition, we have used real-time imaging strategies to show that hematopoietic stem cells have
            the capacity to undergo both symmetric and asymmetric division, and that shifts in the balance
            between these modes of division are controlled by the microenvironment and subverted by
            oncogenes. Most recently, we have developed a high resolution in vivo imaging system that has
            allowed us to begin to map the behavior and interactions of hematopoietic stem cells with the
            microenvironment within living animals, and define how these change during regeneration and
            cancer formation.
            Panel Discussion:
            Moderator: Yi Liu, Ph.D. Vice President, Intellikine
            Panelists:
            David Cheresh, Ph.D.
            Professor of Pathology, Associate Director for Translation Research, Moores UCSD Cancer
            Center
            Greg Reyes, M.D., Ph.D.
            Senior Vice President, Drug Discovery, Celgene
2:05-3:05
            Isan Chen, M.D.
            Chief Medical Officer, Aragon
            Jeremy Barton, M.D.
            Vice President Precision Medicine, Pfizer
            Steve Kaldor, Ph.D.
            Venture Partner at Versant Ventures, acting CEO, QuantiCel
            Tannishtha Reya, Ph.D
            Professor, Department of Pharmacology, UCSD
3:05-3:10   Closing Remarks: Wen Luo Ph.D., CSO, Denovo Biomarkers
       www.SABPA.org | Science & Technology Forum X




David Cheresh, Ph.D., Professor of Pathology, Associate Director for Translation Research, Moores
UCSD Cancer Center
                                David Cheresh studies the mechanism of action of signaling networks
                                that regulate cancer growth and metastasis and focuses on new
                                strategies for biologically-based drug development. In particular, he
                                studies how integrins and growth factor receptors promote, cell
                                survival, angiogenesis and tumor invasion. His work has lead to the
                                development of several drugs now in various stages of clinical
                                development. Cheresh together with scientists at Applied Molecular
                                Evolution developed a humanized antibody (Vitaxin) directed to
                                integrin avb3 which is now being developed by Astra Zeneca. In
                                collaboration with Merck Darmstadt, Cheresh developed an integrin
                                antagonist (Cilengitide) targeting integrins  and  that has
                                now produced significant survival benefit in glioblastoma patients and
                                has lead to the first integrin targeted drug to enter Phase III clinical
                                trials for cancer. David Cheresh was the scientific founder of
                                TargeGen, a San Diego based Biotechnology Company which
                                developed a number of small molecules based in part on discoveries
                                made in the Cheresh laboratory. Recently, TargeGen was acquired by
                                Sanofi Aventis who is developing a highly selective JAK2 inhibitor
                                discovered by TargeGen scientists. Most recently, Cheresh and his
                                colleagues have developed a novel scaffold based chemistry approach
                                to stabilize kinases in their inactive state. These studies have lead to
                                the discovery of a first in class Raf inhibitor that has distinct
                                advantages relative to ATP mimetics of RAF. Cheresh and his
                                colleagues at UCSD have founded a new start up company (Amitech
                                Therapeutic Solutions) which focuses on the discovery of allosteric
                                inhibitors of kinases such as those targeting Raf and other important
                                molecules/pathways relevant to cancer and inflammatory disease.

Greg Reyes, M.D., Ph.D., Senior Vice President, Drug Discovery, Celgene

                                Greg Reyes, M.D., Ph.D. has nearly 25 years of experience in
                                biotechnology and the
                                pharmaceutical industry. He has held senior leadership roles at
                                companies like Biogen Idac, Cyclacel, Pfizer and Schering-Plough.
                                He currently holds the position of Senior VP for Drug Discovery with
                                Celgene at their San Diego campus. After obtaining his M.D. and
                                Ph.D. at Johns Hopkins in Baltimore, MD he did medical and
                                postdoctoral training at Stanford’s University hospital and then with
                                the late Henry Kaplan at his Cancer Biology Research Lab as a
                                Damon Runyon Cancer Research fellow. His career in industry has
                                spanned virus ‘discovery’ and characterization (non-A, non-B viruses
                                and gastroenteritis agents) to small molecule and biologics drug
                                discovery and development in a number of different therapy areas.
                                Greg has also been active as an advisor and past member of a number
       www.SABPA.org | Science & Technology Forum X
                                 of senior advisory councils including the National Advisory General
                                 Medical Sciences (NAGMS) Council, Past Chair of the External
                                 Advisory Committee to the International Outreach Program (IOP), St.
                                 Jude Children’s Research Hospital and past member of the Standing
                                 Review Committee for Research Centers in Minority Institutions
                                 (RCMI), National Center for Research Resources, National Institutes
                                 of Health.
Jean Cui, Ph.D., Associate research fellow, Pfizer

                                   Dr. J. Jean Cui is currently an Associate Research Fellow and project
                                   leader at Pfizer La Jolla R&D Center. Jean has more than 16 years
                                   experience in drug discovery, especially in oncology field. Jean is the lead
                                   inventor of Crizotinib (brand name XALKORI), which was granted fast
                                   track approval by FDA on Aug. 26th, 2011 for ALK positive late stage non
                                   small cell lung cancer. The drug is a major breakthrough of personalized
                                   and genomic medicine. Jean worked on several other oncology projects,
                                   including SUTENT project. Another milestone clinic c-Met specific inhibitor
                                   PF-04217903 also came from Jean’s creative design. Jean received
                                   Pfizer Global R&D Achievement Award for her significant contributions and
                                   leadership in generating two clinical candidates PF-02341066 (Crizotinib)
                                   and PF-04217903. Jean and her Crizotinib chemistry team were selected
                                   as the 38th National Inventor of the Year Award in 2011 by the Intellectual
                                   Property Owners Association. Jean is the author or co-author of more
                                   than 50 publications and patents. Jean conducted her postdoctoral
                                   research at Lawrence Berkeley National Laboratory/University of California
                                   Berkeley. She earned her Ph.D. in Organic Chemistry from Ohio State
                                   University under the direction of Professor Derek Horton. Jean received
                                   her B.S. and M.S. in Chemistry from University of Science and Technology
                                   of China.

Steve Kaldor, Ph.D., Venture Partner at Versant Ventures, acting CEO, QuantiCel

                                   Dr. Kaldor is the CEO of Quanticel, a privately held cancer drug discovery
                                   company, and is also a Venture Partner at Versant Ventures. From 2007
                                   – 2010 he served as President & CEO of Ambrx, a pioneering biologics
                                   company. Dr. Kaldor was President & CSO of Syrrx, a structure-based
                                   drug discovery company, from 2002 – 2005 and led this company through
                                   its $270M acquisition by Takeda (2005) and for several years post
                                   acquisition. Prior to joining Syrrx, he gained 12 years of R & D experience
                                   at Eli Lilly and Company as both a researcher and Director. Dr. Kaldor is a
                                   chemist by training (Columbia; Harvard) and is an inventor of the marketed
                                   drugs ViraceptTM (AIDS) and NesinaTM (diabetes) plus multiple additional
                                   drug candidates that have advanced into Development. He has also
                                   contributed to the maturation of various other companies as an
                                   independent board member including Amira (2011 acquisition by BMS),
                                   Anaphore, and Furiex (NASDAQ: FURX).



Jing Yang, Ph.D., Assistant professor of pharmacology and pediatrics, UCSD
       www.SABPA.org | Science & Technology Forum X
                                  Dr. Jing Yang is currently an Assistant Professor in Department of
                                  Pharmacology and Pediatrics in University of California, San Diego. Jing
                                  received her PhD training on Molecular Cancer Biology from Duke
                                  University in 1999 after completing her undergraduate training in University
                                  of Science & Technology of China. She then had her postdoctoral training
                                  in Dr. Robert Weinberg’s lab in Whitehead Institute for Biomedical
                                  Research during 2000-2006. She has more than 27 publications in peer-
                                  reviewed journals. She is the first person reported TWIST Plays an
                                  Essential Role in Tumor Metastasis in Cell in 2006. Jing Joined
                                  Department of Pharmacology in UCSD in 2006. The focuses of her
                                  research are: 1. Dissect the signaling pathways that link Twist to EMT and
                                  tumor metastasis. 2. Determine how activation of Twist and EMT promotes
                                  tumor metastasis in vivo. 3. Develop new mouse models to label, image,
                                  and study migrating carcinoma cells in vivo


Isan Chen, M.D., Chief Medical Officer, Aragon




                                  Isan Chen, M.D. is presently the CMO of Aragon Pharmaceuticals, a
                                  privately owned biotech company in San Diego focused on therapies
                                  targeting hormone-driven cancers. He is a board certified hematologist-
                                  oncologist with more than 12 years of oncology experience. Previously, he
                                  was Vice-President, Genitourinary Tumor Strategy Leader for Pfizer
                                  Oncology. He completed his hematology-oncology fellowship at University
                                  of California, San Diego and served as a faculty member in the
                                  Department of Genitourinary Medical Oncology at the University of Texas,
                                  MD Anderson Cancer Center.




Tannishtha Reya, Ph.D, Professor, Department of Pharmacology, UCSD



                                  Tannishtha Reya is a Professor of Pharmacology at the University of
                                  California, San Diego School of Medicine and an Adjunct Professor at the
                                  Sanford-Burnham Medical Research Institute. Prior to moving to San
                                  Diego, she served as an Associate Professor of Pharmacology and
                                  Cancer Biology and Co-director of the Stem Cell and Regenerative
                                  Medicine Program at Duke University. Dr. Reya obtained her bachelor’s
                                  degree from Williams College and her Ph.D. from the University of
                                  Pennsylvania. She subsequently completed postdoctoral training at UCSF
                                  and Stanford University. Her work has provided insight into the signals
                                  that control stem cell growth, and how the same signals are subverted to
                                  fuel cancer growth. Her awards include the Leukemia and Lymphoma
                                  Society Scholar award, the Presidential Early Career Award for Scientists
                                  and Engineers and the Pioneer Award.



Jeremy Barton, M.D., Vice President Precision Medicine, Pfizer
       www.SABPA.org | Science & Technology Forum X
                                  Jeremy Barton obtained a Masters degree in Physiological Sciences
                                  from Oxford University and graduated from University College
                                  Hospital Medical School, London. After training in Internal
                                  Medicine he specialized in Clinical Oncology in the UK achieving
                                  Specialist status in this area and practiced for 11 years in the
                                  National Health Service. He is a Member of the Royal College of
                                  Physicians (UK), a Fellow of the Royal College of Radiologists
                                  (Oncology) and a Member of the Faculty of Pharmaceutical
                                  Medicine. 1992 he joined the pharmaceutical industry and in the last
                                  20 years has held a variety of positions in the field of Oncology
                                  including both big pharma companies in Switzerland and the UK,
                                  biotech companies in the US and had his own consulting business.
                                  Currently employed as Vice President, Precision Medicine, Pfizer
                                  WRD, his special interest is the interface between Research and
                                  Early Development through to Proof of Concept with emphasis on
                                  integration of a companion diagnostic strategy into drug
                                  development plans.
Laure Escoubert-Lozach, Ph.D., Senior Scientist, Celgene

                                  Laure Escoubet-Lozach has been a senior scientist in Celgene’s
                                  Drug Discovery Oncology department since 2006. Her first
                                  assignment was to investigate the role of epigenetics in the
                                  mechanism of action of the company’s immunomodulatory
                                  compounds known as IMiDs®. She played a key role in the creation
                                  of the Epigenetic group within Celgene Discovery, focused on
                                  identifying and validating epigenetic targets, as well as supporting
                                  the pre-clinical development of small molecule inhibitors against
                                  these targets. She is currently coordinating the biology effort for one
                                  epigenetic program and leads the epigenetic profiling efforts for
                                  Discovery’s in-house cancer stem cell programs.
                                  Prior to Celgene, Dr Escoubet-Lozach did her post-doctoral training
                                  at the University of California, San Diego, in the laboratory of
                                  Christopher K. Glass. There, she pioneered genome-wide epigenetic
                                  studies in inflammation, investigating the regulation of chromatin
                                  modifications in macrophages and the orchestrated program that
                                  controls gene expression in these cells.
                                  Laure received her PhD in Human Patho-Physiology from the
                                  University Paul Sabatier in Toulouse, France.
      www.SABPA.org | Science & Technology Forum X

                                      ORGANIZERS
      SINO-AMERICAN BIOMEDICAL AND PHARMACEUTICAL PROFESSIONALS
                          ASSOCIATION (SABPA)

                         Event Committee
                            Yi Liu    Intellikine

                         Wen Luo      Denovo Biomarkers

                      Marie Zhang     MicroStem

                        Hua Gong      Medical Diagnostics Premier Research Group

                         Tao Wu       Life Technology

                      Xiaohu Deng     J&J PRD

                        Zheng Xu      Illumina

                         Heng Dai     J&J PRD

                        Yahua Liu     GNF

                     Li-Ming Liang    Abgent, a WuXi AppTec Company

                       Feng Yang      Consultant

                         Yang Liu     Burnham Institute

                    Yinghong Gao      EMD Millipore

                        Peter Zhu     Pfizer



Supporting Team
  Xuefeng Zhu         Yuan Liu                      Jung Yang             Oliver Long
  Xin Zhao            Julie O’brien                 Zhijiang Chen         Bhawanjit Brar
  Jiang Hao           Allan Pan                     Zhaohui Dong          Bohan Stan Jin
  Jennifer Lin        Guangwen Wang                 Jiayi Yang            Xianbo Zhou
  Shanshan Yan        Holly Jing                    Yuan Liu              Hong Qi
  Sherry Zhao
www.SABPA.org | Science & Technology Forum X

                             Sponsors

								
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