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 Stay on to attend Structure-Based Design (June 6 - 8)

Sunday, June 3

5:00–6:00 pm Early Conference Registration

Monday, June 4

7:30 am Registration and Morning Coffee

8:30 Chairperson’s Opening Remarks

8:35 Discovery of Novel Classes of Orally Bioavailable Kinase Inhibitors which Inhibit TIE-2
Richard Luke, Ph.D., CIRA, AstraZeneca
Tie-2 is a tyrosine kinase that is believed to be involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazolealkene- pyrimidine kinase inhibitors is reported that inhibit Tie-2 in vitro and in cells. These compounds are lead-like, with low molecular weight, good physical properties, oral bioavailability and in vivo activity. Developments in this series leading to further novel series of kinase inhibitors will be discussed. Issues with showing in vivo activity of Tie-2 inhibitors will be addressed.

9:05 Kinase Targets Involved in Cancer Progression
Richard Klemke, Ph.D., Department of Pathology, University of California, San Diego
We have used large scale quantitative mass spectrometry and IMAC to identify unique kinases and substrates of kinases that are altered during cancer progression and cell metastasis. We have identified a novel cytoskeletal associated tyrosine kinase that mediates cancer cell invasion. This enzyme is upregulated in metastastic colon and pancreatic cancer cells in 70-80% of patients. This kinase is an excellent biomarker and target for drug discovery.

9:35 Fragment-Based Discovery of Selective, Orally Bioavailable Tyrosine Kinase Inhibitors for Targeted Treatment of Human Cancers
Stephen K. Burley, Chief Scientific Officer and Senior Vice President Research, SGX Pharmaceuticals, Inc.
SGX Pharmaceuticals, Inc. (SGX) has developed a fragment based drug discovery platform that utilizes high-throughput X-ray crystallography for lead identification/optimization. The proprietary FAST™ (Fragments of Active Structures) process exploits crystallographic screening to detect, visualize, identify and optimize small ligands (MW 150-200) that are bound to the target protein. Successful applications
of the FAST™ fragment-based lead discovery/optimization process will be presented for a portfolio of well validated oncology targets.

10:05 Coffee Break, Exhibit and Poster Viewing

10:45 EphB/RAF Kinase Inhibitors for the Treatment of Cancer
Alcide Barberis, Ph.D., Chief Executive Officer, Oncalis AG
Through a novel yeast cell-based assay applied to a high-throughput screen (HTS) we have selected kinase inhibitors that target members of the EphB receptor tyrosine kinase family as well as the key cytoplasmic kinases RAF. The positive read-out of the applied cellular HTS rapidly selects for multi-target kinase inhibitors that are endowed with favorable properties such as cell permeability, solubility and metabolic stability, and against generally cytotoxic compounds, thus significantly facilitating hit to lead optimization. Consistent with this selection step, further characterization of the EphB/RAF inhibitors, which inhibit both kinase types with IC50 of ~200nM, showed good stability in human hepatocytes, as well as oral bioavailability and appropriate pharmacokinetics in mice. The selectivity profile of these inhibitors is particularly favorable to their application for the treatment of selected tumors. Preclinical data will be presented and discussed.

11:15 Technology Highlights (Sponsorship Available)

11:30 BLOCK or LOCK: Complementary Approaches to Targeting Macromolecular Interactions
David Borhani, Ph.D., Group Leader, Department of Chemistry, Abbott Bioresearch Center

11:45 Discovery of Novel Potent and Selective Polo-Like Kinase Inhibitors
Campbell McInnes, Ph.D., Assistant Professor, Pharmaceutical Sciences, University of South Carolina
Polo like kinases (Plks) have numerous functions in mitosis, are overexpresssed in many tumor types and are thus considered to be validated anti-tumor targets. Small molecule Plk inhibitors would therefore be beneficial in the development of targeted cancer therapeutics and should also be valuable as probes to determine cellular phenotypes of Plk inhibition. Through homology modelling of the Plk1 kinase domain, a chemical series based on benzthiazole N-oxide, has been discovered that displays potent and selective Plk1 inhibition. The effects of an optimized analogue, Cyclapolin 1 on purified centrosomes, indicate that Plks are required to generate MPM2 epitopes, recruit gamma-tubulin and enable nucleation of microtubules. Treatment of living S2 cells with Compound 1 leads to collapsed spindles in contrast to the metaphase arrested bipolar spindles seen following RNAi. The differential cellular response to protein depletion and protein inhibition and impact on the development of anti-tumour agents is discussed.

1:40 Chairperson’s Remarks

1:45 Dlgh1 MAGUK Coordinates “Alternative” p38 Activation, Directing Proximal TCR Kinases to Activation of NFAT, but not NFkB
M. Carrie Miceli, Ph.D., Associate Professor, MIMG, UCLA
Tyrosine kinase activation couples TCR engagement to discrete signaling cascades capable of differentially contributing to functional outcome. However, mechanisms of channeling TCR signals toward specific targets remain undefined. TCR stimulation utilizes MKK independent “alternative”-p38-activation, whereby Lck/Zap70 directly activate p38 activation. We report that alternatively-activatedp38 associates with Dlgh1 and have identified Dlgh1/Lck/ZAP70 complexes, raising the possibility that Dlgh1 coordinates alternative-p38-activation. Manipulation of T-cell Dlgh1 levels affects alternative-p38 and NFAT, but not JNK or NFkB, activation. p38-binding-deficient-Dlgh1 can not support p38 or NFAT activation and p38 inhibitor ablates Dlgh1-NFAT upregulation. Therefore, Dlgh1 selectively couples proximal TCR-kinases to p38-mediated NFAT activation. Together with reports that CARMA1 coordinates JNK and NFkB, but not p38 or NFAT activation, our findings identify MAGUKs as orchestrators of TCR signal specificity.

2:15 Translational Studies with the EGFR Inhibitor Erlotinib
Neil Gibson, Ph.D., Chief Scientific Officer, OSI Pharmaceuticals, Inc.
Perhaps the greatest improvement in the treatment of advanced non-small cell lung cancer (NSCLC) patients has been achieved with the EGFR inhibitor erlotinib. In a 2nd and 3rd line setting (the BR21 trial) erlotinib was found to increase survival in a large unselected patient population with a very acceptable side effect profile. Numerous clinical and translational studies are helping to increase our understanding of “biomarkers” that may be useful in either selecting patients for future trials or that can help us measure response to therapy. As we better understand the signaling pathways in which these biomarkers are involved we are likely to be able to design better and more relevant combinations of molecular targeted therapies.

2:45 Purine-Based Inhibitors of Bcr-Abl and its Mutants
Yihan Wang, Ph.D., Principal Scientist, Department of Chemistry, ARIAD Pharmaceuticals, Inc.
Purine and so-called Morphed purines are common templates for therapeutic agents, especially targeted agents as protein kinase inhibitors. ARIAD over the years developed several purine-based chemotypes as dual Src/Abl kinase inhibitors for CML and cancer metastasis. For CML, emergence of resistence to the current agent Gleevec poses big challenge to the current treatment, mainly due to the fact that point mutations in the catalytic domain renders the drug inactive. Effective strategies were developed to combat the resistence, one among them is the development of potent dual Src/Abl inhibitors. Through our program of structure-guided design, we have identified a series of compounds that inhibit most of the mutant including T315I both in vitro and in vivo. Such compounds have the potential to become effective treatment for Gleevec refractory CML and other cancer.

3:15 Refreshment Break, Exhibit and Poster Viewing

4:00 “Addiction” to Oncogenic Kinases in Human Cancer
Jeffrey Settleman, Ph.D., Professor of Medicine, Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School
We have identified a class of activating mutations of the epidermal growth factor receptor (EGFR) gene in human lung tumors, whose presence is correlated with dramatic clinical responses to selective EGFR kinase inhibitors in a subset of treated patients. Although clinical responses can be rapid and dramatic, the average duration is only ~6 months due to acquired drug-resistance, and we have begun to identify mechanisms by which resistance to drug treatment can arise. In addition, our studies of “oncogene addiction” have led to a novel hypothesis regarding the mechanism by which tumor cells are killed in response to molecularly targeted drug treatments, which we describe as “oncogenic shock,” and may have implications for strategies to target human cancers therapeutically.

4:30 In vivo Genetic Approaches to Identify Mechanisms of Resistance to Inhibition of ErbB-family Receptor Tyrosine Kinases
Ronan O’Hagan, Group Leader, Target Validation/Biology, AVEO Pharamaceuticals, Inc.
This presentation describes an in vivo genetic screen to identify novel cancer targets including kinases. Moreover, the context of the genetic screen, and subsequent work-up of specific receptor-tyrosine kinase targets illustrate alternative pathways that circumvent current therapeutic targets and therefore represent genetic mechanisms of acquired or de novo drug resistance. Hence these proteins enable a priori identification of the genetic context of patients in which current therapeutics are likely to fail or succeed. Moreover, these proteins themselves represent candidate targets in cancers that are, or become, resistant to inhibition of the primary driving oncogene.

5:00 Happy Hour in Exhibit Hall

6:00 End of Day One