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Mastering Medicinal Chemistry 

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Thursday, February 23

 

HOT TARGETS IN CANCER: KINASES AND Hsp90

8:30 am Chairperson's Remarks

Mark Ashwell, Ph.D., Vice President, Medicinal Chemistry, ArQule, Inc.

8:35 Discovery of PI3K Inhibitors Based on the 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine Scaffold with Improved in vivo Anti-Tumor Activity Due to Increased Unbound Drug Exposure

Chudi O. Ndubaku, Ph.D., Scientist, Discovery Chemistry, Genentech, Inc.

Aberrant signaling through the PI3K/AKT/mTOR pathway has been correlated with uncontrollable tumor proliferation and overall poor prognosis in cancer patients.  As such, PI3-kinase inhibitors stand as very promising therapeutics for the treatment of various types of cancers.  We recently discovered novel inhibitors of these enzymes based on the benzoxepin chemical structure.  These inhibitors are very potent, highly selective and have favorable in vivo pharmacokinetic profiles.  We will reveal our approach that combined both structure-guided and physicochemical property-based design to optimize unbound drug exposure in order to derive compounds that effectively suppressed the growth of tumors in mouse xenograft models.

9:05 Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Pan Class I PI3K Inhibitor for the Treatment of Cancer

Sabina Pecchi, Ph.D., Senior Investigator I, Global Discovery Chemistry, Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research

The PI3K pathway is frequently de-regulated in tumors. This presentation describes the structure guided optimization of a series of 2-morpholino pyrimidines PI3K inhibitors culminating in the discovery 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (NVP-BKM120) currently undergoing Phase II clinical trials for the treatment of cancer.

Sponsored byBioScale9:35 The RAS-MAPK and PI3K-AKT Cascades: Novel Assays for Detection and Quantitation of Key Phospho Proteins- Part IIW. Matthew Dickerson, Ph.D., Senior Scientist, BioScale, Inc.The RAS-MAPK and PI3K-AKT pathways are involved in signaling cascades that control numerous physiological and pathological processes.  This study elucidates the selectivity and sensitivity of a novel assay platformfor analysis of phosphoproteins including pAKT, pALK, pERK, pJNK, pp38, pMEK.


10:05 Activation-State Dependent Conformational Differences in Protein Kinases and the role of Hydrophobic Motifs in Inactive Kinases: Lessons Learned in Drug Discovery and Optimization

Mark Ashwell, Ph.D., Vice President, Medicinal Chemistry, ArQule, Inc.

The presentation will describe the utilization of a new understanding of the role of hydrophobic residues within the ATP-binding cleft of inactive protein kinases in order to discover novel inhibitors.  Strategies will be presented and discussed for the identification and optimization of small molecule inhibitor of several kinases e.g., c-Met, FGFR, AKT and others.  Characterization of the molecular interactions with inactive kinases will be described using biophysical, biochemical and cell-based assays together with X-ray crystallographic and mutational studies.  Through the application of this knowledge ArQule has established a new paradigm for kinase inhibitor discovery and will present results on its impact in increasing efficiency and effectiveness in discovery and development.

10:20 Coffee Break

11:00 Discovery of NVP-HSP990, A Potent Oral Inhibitor of Hsp90 in Phase I Clinical Trials

Tim Machajewski, Ph.D., Global Discovery Chemistry, Novartis Institutes for BioMedical Research

Hsp90 is a molecular chaperone whose function is essential for activity of tumorigenic signaling molecules. This presentation describes the structure guided optimization of aminodihydroquinazolinone Hsp90 inhibitors culminating in the discovery of NVP-HSP990, undergoing Phase I trials for treatment of cancer.

11:30 Understanding Structure Intricacies of Protein Kinases:  The Road to Invention of c-Met/ALK Dual Inhibitor Crizotinib

Jean Cui, Ph.D., Associate Research Fellow, Oncology Medicinal Chemistry, Pfizer Global R&D

In-depth understanding of the characteristics of targeted protein kinase is essential for the invention of kinase drugs with high quality drug-like properties.  2-Amino-5-aryl-3-benzyloxypyridine scaffold was created based on the autoinhibitory conformation of c-Met, and optimized to generate Xalkori (Crizotinib, PF-02341066) as a potent and highly selective c-Met/ALK dual inhibitor with good pharmaceutical properties.

HOT TARGETS IN INFLAMMATION, ALLERGY AND DIABETES

12:00 pm The Discovery and Development of ARRY-502: A Potent, Selective CRTh2 Antagonist for Allergic Diseases

Larry Burgess, Ph.D., Senior Director, Medicinal Chemistry, Array BioPharma

Selective antagonism of the Prostaglandin D2 receptor (CRTh2) offers a new therapeutic approach for the treatment of allergic disease. CRTh2 is expressed in eosinophils, basophils and Th2 T cells and mediates activation and chemotaxis.  Our drug discovery efforts focused on substituted phenyl acetic acids that ultimately lead to the identification of ARRY-502, a potent, selective CRTh2 antagonist. Subsequent phase I clinical studies have now demonstrated that ARRY-502 is well tolerated and possesses excellent human pharmacokinetics along with prolonged pharmacodynamic activity.  ARRY-502 is advancing to Phase 2 for asthma.  

     Sponsored bySchrodinger 12:30 Rapid Drug Discovery at Nimbus and the Role of SeuratMatt Wessel, Senior Principal Scientist, Seurat Applications Support, Schrodinger 

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:45 Chairperson's Remarks

Larry Burgess, Ph.D., Senior Director, Medicinal Chemistry, Array BioPharma

1:50 The Discovery of MK-7725, a Potent and Selective Bombesin Receptor Subtype-3 (BRS-3) Agonist for the Treatment of Obesity

Harry Chobanian, Ph.D., Research Fellow, Discovery Chemistry, Merck Research Labs

The BRS-3 receptor is an orphan GPCR expressed primarily in the hypothalamus region of the brain and has been implicated to regulate food intake and metabolic rate. This presentation outlines the effort that led to the discovery of MK-7725 for the treatment of obesity.

HOT TARGETS IN CNS

2:20 Selective JNK Inhibitors for the Prevention of Neurodegeneration

Simeon Bowers, Ph.D., Staff Scientist, Medicinal Chemistry, Elan Pharmaceuticals

The development of a series of selective JNK inhibitors is described. Optimization of the HTS hit led to single digit nanomolar compounds with improved pharmacokinetic properties and greater CNS exposures. Optimized compounds were active in neurotoxicity assays and lowered levels of phospho-c-Jun in the brain in a kainic acid model of neuro-inflammation.

2:50 Inhibiting Caspases in New and Unexpected Ways

Brian Hearn, Ph.D., Medicinal Chemistry, Small Molecule Discovery Center, University of California, San Francisco

Caspase-6 plays a key role in the neurodegeneration associated with Huntington's disease. Our efforts to identify new caspase-6 inhibitors led to the discovery of non-covalent and non-ionic compounds that demonstrate substrate-dependent inhibition. This presentation will focus on lead optimization and mechanism of action studies.

3:20 Close of Conference



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