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Thursday, March 27

8:25am Chairperson's Remarks 
David A. Price, Ph.D., Director, Cardiovascular Metabolic and Endocrine Diseases Chemistry, Pfizer Global Research and Development

8:30 Tykerb and Beyond
Dirk Heerding, Ph.D., Director, Chemistry, Oncology CEDD, GlaxoSmithKline

9:15 CCR5 Antagonists for the Treatment of HIV; The Discovery of Maraviroc
David A. Price, Ph.D., Director, Cardiovascular Metabolic and Endocrine Diseases Chemistry, Pfizer Global Research and Development
It is estimated that globally 42 million people are currently infected with HIV and it is the biggest infectious disease killer in the world with 3 million deaths per year attributable to HIV. The disease is world-wide, with sub-Saharan Africa being the worst affected area with >25million individuals infected; in North America there are over 1million infected individuals. There have been tremendous advances in the treatment of HIV, however, due to emerging resistance profiles there is a still a strong need for new mechanisms of action for the treatment of HIV. In particu-lar targeting proteins expressed by the host rather than the virus has been an intense area of research for the last decade. Many research groups have focussed on the CCR5 receptor as a key target; this receptor is expressed by human defence cells and is a key protein enabling HIV fusion with these cells to initiate replication. This talk presents the challenges that were faced and successfully overcome in the discovery phase of maraviroc, in particular balancing the problems of pharmacokinetics, hERG pharmacology, antiviral potency and resistance profile. The trans-lation of the preclinical profile into the Phase 3 data will also be discussed, which shows maraviroc to be a highly exciting addition to the treatment options for HIV.

10:00 Technology Spotlight (Sponsorship Available)

10:15 Technology Spotlight (Sponsorship Available)

10:30 Poster Competition & Refreshment Break in the Exhibit Hall

11:30 Histone Deacetylase Inhibitors: Bench to Bedside
Thomas A. Miller, Ph.D., Head of HDAC Chemistry, Merck Research Laboratories
HDAC inhibitor lead structures have provided effective platforms for structural optimization, affording HDAC inhibitors with sub-nanomolar HDAC enzyme inhibitory activities. Hydroxamic acids constitute the largest chemical class of HDAC inhibitors and these agents are among the most potent HDAC inhibitors known. The discovery and development of Zolinza?(SAHA, vori-nostat), a novel hydroxamic acid derived HDAC inhibitor, along with relevant background and recent advances in HDAC inhibitor design, will be presented. 

12:00pm Sagopilone (ZK-EPO): From a Natural Product to a Fully Synthetic Clinical Development Candidate
Ulrich Klar, Ph.D., Project Leader, Medicinal Chemistry, Bayer Schering Pharma AG
The highly convergent and efficient synthetic approach towards sagopilone, the first fully synthetic, third generation epothilone in clinical trials, via three building blocks is reported. Preclinical data of sagopilone in comparison to paclitaxel and other epothilones currently in clinical trials by competitors will be presented and discussed. The development compound sagopilone has evolved from the subsequent pharmacological studies as a highly potent, apoptosis-inducing anti-cancer agent and is currently investigated in a robust Phase II clinical trial program.

LUNCHEON TECHNOLOGY WORKSHOP 12:30 Presentation I: AllChem: Idea Generator for Medicinal Chemists Sponsored by Tripos Richard D. Cramer, CSO, Tripos, Inc. A good medicinal chemistry idea should provide: the best chances for the desired biological profi le; structural novelty; synthetic feasibility; drug-like-ness; and be hassle-free to obtain. The search results to be shown in a live demonstration of the AllChem system on a laptop will be based on selections among queries that attendees submit in advance. Your candidate query structure can be sent to cramer@tripos.com. 1:00 Presentation II (Sponsorship Available)

1:30 Break

1:45 Chairperson's Remarks 
Mark A. Ashwell, Ph.D., Vice President, Chemistry, ArQule Inc.

1:50 SAR in the Area of Antibody-Targeted Chemotherapy: Mylotarg and other Calicheamicin Conjugates
Philip R. Hamann, Ph.D., Principal Research Chemist, Wyeth Research
The CD33-targeted antibody-calicheamicin conjugate Mylotarg is the only approved antibody-directed chemotherapeutic agent in oncology, in spite of many years of research on antibody conjugates in general and the many cytotoxic agents that have been examined for this approach. The history of Mylotarg and how the optimized linker and calicheamicin derivatives were chosen will be discussed, as well as current applications of this technology. Observations of current developments in this field and implications for the future will also be included.

2:20 The Discovery and Early Development of ARQ 197, a Selective c-Met Inhibitor
Mark A. Ashwell, Ph.D., Vice President, Chemistry, ArQule Inc.
ARQ 197 is a novel orally bioavailable small molecule c-Met receptor tyrosine kinase inhibitor advancing into Phase 2 clinical trials. This presentation will describe the identification of ARQ 197 and its pre-clinical characterization in a variety of in vitro and in-vivo assays. ARQ 197 was well-tolerated in Phase 1 trials and has exhibited signs of tumor response in late stage cancer patients with metastatic disease and these results will also be presented.

2:50 Discovery and Development of Potent and Highly Selective c-Met/HGFR Inhibitors
Robert Kania, Ph.D. Senior Director, Oncology chemistry, Pfizer, Inc.
c-Met receptor tyrosine kinase is an attractive oncology target due to the critical role of aberrant HGF/c-Met signaling in human oncogenesis and tumor invasion/metastasis. A number of c-Met inhibitors have been discovered at Pfizer with different product profiles. The clinic candidate PF-2341066 demonstrated potent in vitro and in vivo c-Me inhibition, good selectivity profile, effective tumor growth inhibition, and good pharmaceutical properties. 

3:20 Plenary Keynote 

4:00 Ice Cream Refreshment Break in the Exhibit Hall with BEST OF SHOW AWARDS

4:45 Steroid Sulfatase Inhibition: From Concept to Clinical Trial 
Lawrence Woo, Ph.D., Project Leader and Operational Manager, Department of Pharmacy and Pharmacology, University of Bath; and Sterix Ltd., a member of the Ipsen
Inhibition of steroid sulfatase has emerged as a novel and promising anti-endocrine strategy for the treatment of hormone-dependent breast cancer. A steroid sulfatase inhibitor renders estro-gen deprivation through inhibiting steroid sulfatase, which hydrolyses the biologically inactive steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate, to their correspond-ing unconjugated steroids. These products, either themselves or through their metabolites, provide the estrogenic stimulation required for the growth and development of a tumor. We will highlight the discovery of sulfamate-based steroid sulfatase inhibitors and their successful evolution from an early steroidal lead to the nonsteroidal �First-in-Class�Eclinical trial candidate STX64 (BN83495). Aspects of drug delivery, pharmacokinetics, preclinical development and Phase I results of the drug will be presented. Several innovative spin-out projects from the original con-cept of steroid sulfatase inhibition will also be discussed.

5:15 Discovery of Benzodiazepinone Inhibitors of the p53:HDM2 Interaction
Mark R. Player, M.D., Ph.D., Research Fellow & Team Leader, Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, result-ing in the discovery of a novel series of benzodiazepinone antagonists of the HDM2�p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 revealed their alpha-helix mimetic properties and guided a structure-based design lead optimization program. These optimized molecules increase the transcription of p53, induce the translation of p53 target genes, decrease the proliferation of tumor cells expressing wild-type p53 and showed synergistic activity with doxorubicin both in vitro and in an A375 melanoma xenograft model.

5:45 End of Day