Main Conference

10月 21日 (火)

7:00am – 6:30pm Registration Open

7:30am Morning Coffee

LEAD OPTIMIZATION

- リード化合物の最適化 -

8:30 Chairperson's Remarks 
Stephen K. Burley, Ph.D., Chief Scientific Officer and Senior Vice President, SGX Pharmaceutical

8:40 Dissecting Kinase Inhibitor Activities by Genome-Wide Dose Response Analysis
Rui-Ru Ji, Ph.D., Senior Research Investigator, Applied Genomics, Bristol-Myers Squibb
We have devised a new strategy that exploits compound activities across a wide dose range. New analytical methods have been developed to identify genes that exhibit sigmoidal dose response and map them to signaling pathways and other cellular processes. We find that the approach can help dissect distinct compound activities by mapping these activities to different compound concentrations, thereby uncovering the mechanism of action and potential compound poly-pharmacology.

9:10 Discovery of MP-529: A Selective Inhibitor of Aurora 2 Kinase in Development for the Treatment of Cancer
Hariprasad Vankayalapati, Ph.D., Director of Medicinal Chemistry, SuperGen Inc.
As a part of our oncology drug development program to identify small molecule kinase inhibitors, we have initially identified a very selective sub-nanomolar inhibitor of the pyrimido[4,5-b]indole class of Aurora-A kinase using a de novo fragment-based design strategy by utilizing X-ray crystal structure of an Aurora-A kinase. To further validate the inhibitory effect of this initial lead molecule, it was subjected to several cell-based assays in which it exhibited activity in the mid- to high-micromolar range. These results suggest that the lead compound is effectively hitting the intended cellular target and that lead optimization will likely be required to produce greater cellular potency. Therefore, we have employed lead optimization and successfully synthesized several compounds that led to the identification of MP-529 potent and selective Aurora A kinase inhibitor that belong to pyrimido[4,5-b]indoles series. Based on its high Aurora-A selectivity and antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in-vivo tumor models, the compound MP-529 was ultimately selected for further development.

9:40 Clinical Experiences with a Selective, Orally Bioavailable MET Receptor Tyrosine Kinase Inhibitor for Targeted Treatment of Human Cancers
Stephen K. Burley, Ph.D., Chief Scientific Officer and Senior Vice-President, SGX Pharmacueticals, Inc.

10:10 Grand Opening Coffee Break in the Exhibit Hall

10:40 The Role of Biomarkers in Kinase Inhibitor Development:  Pharmacodynamic and Predictive Clinical Studies
Jason Hill, Ph.D., Director, Molecular Biology, Targeted Molecular Diagnostics
We will present a strategy of biomarker development from pre-clinical through clinical trial implementation, and how this information can be used to differentiate competitive kinase inhibitors. We will present clinical studies we are currently involved in to measure phosphorylated biomarkers to monitor Src kinase inhibitor pharmacodynamics in patients in real-time to alter the dosing of patients on trial. We will also present biomarker studies we did for GSK's lapatinib (Tykerb) and recent data correlating phosphorylated biomarker expression with patient response and how these studies are possible because of a standardized specimen collection format. We will also discuss how this biomarker data can be integrated to develop a companion diagnostic test to select patients and how this can greatly facilitate FDA approval.

11:10 Talk Title to Be Announced
John Hynes, Ph.D., Bristol-Myers Squibb (tentative)

11:40 Profiling Kinases Directly in Human Tissues with KinobeadsTM
David Simmons, Ph.D., MBA, Chief Scientific Officer, Cellzome
Cellzome has developed a novel approach to kinase drug discovery based on KinobeadsTM that allow direct analysis of kinases in their physiological state isolated directly from human cells and tissues. KinobeadsTM are used to drive potency and selectivity throughout the drug discovery process and are directly applicable to human translational medicine studies. Additionally, they have been used to profile marketed kinase inhibitors - including Gleevec and Sprycell to yield novel insights and targets of these drugs.

12:10pm Panel Discussion:  Do We Need More Targets?

12:40 Luncheon Technology Workshop or Lunch on your Own

1:40 Session Break

RESISTANCE AND SAFETY

- 抵抗性と安全性 -

2:20 Chairperson's Remarks
Ariel Fernandez, Ph.D., Karl R. Hasselmann Chair in Engineering, Professor of Bioengineering, Rice University

2:25 Structure-Guided Design of Inhibitors of Key Bcr-Abl Point Mutations which Confer Resistance to Imatinib
William C. Shakespeare, Ph.D., Senior Director, Chemistry, Ariad

2:55 Translational Ideas to Curb Side Effects in Anticancer Kinase-Targeting Therapy: Reducing Cardiotoxicity through Inhibitor Redesign
Ariel Fernandez, Ph.D., Karl F. Hasselmann Chair in Engineering, Professor of Bioengineering, Rice University
Burgeoning interest in multi-target kinase inhibitors to treat malignancies motivated a re-assessment of the therapeutic value of promiscuity. While drug efficacy may not correlate with specificity, it would be risky to welcome promiscuous compounds without a rational strategy to control therapeutic impact. This situation may change as novel selectivity filters, such as target packing, are incorporated into drug design. For example, the risk of cardiotoxic side effects in the cancer drugs imatinib and sunitinib may be curbed through a redesign guided by the unique packing patterns of their clinically relevant targets. Here I survey approaches to control the therapeutic impact of cross-reactive kinase inhibitors and advocate for the application of a novel selectivity filter by illustrating its “cleaning efficacy”. Finally, I evaluate the possibility to turn multi-target kinase inhibitors into better clinical opportunities through judicious redesign.

3:25 Technology Watch (Sponsorship Available)

3:55 Networking Refreshment Break in the Exhibit Hall

4:30 Targeting the BDNF/TrkB Signal Transduction Pathway; Lessons Learned from Studies on Neuroblastoma Tumors
Carol J. Thiele Ph.D., Head, Cell & Molecular Biology Section, Pediatric Oncology Branch, NIH
Expression of BDNF and TrkB are poor prognostic indicators in the childhood tumor, Neuroblastoma. Studies indicate that activation of this pathway stimulates  angiogenesis  and increases the invasive capacity of neuroblastoma cells. Moreover, both the concentration of TrkB ligands and the relative expression of TrkB  significantly attenuates the effects of standard chemotherapy on neuroblastoma cells. Targeting the BDNF/TrkB pathway  increases the sensitivity of tumor cells to chemotherapy, decreases their angiogenic potential and invasiveness. Although most extensively examined in neuroblastoma, recent studies indicate that activation of the TrkB pathway may play a role in the pathogenesis of prostate, hepatocellular, head and neck, lung and breast cancer

5:00 ex vivo Model of Drug Screening, Toxicology, and Tailored Medicine
Masato Mitsuhashi, M.D., Ph.D., Chief Scientific Officer, Hitachi Chemical Research Center
Our group recently developed a novel assay system, in which the action of kinase inhibitors is quantitatively assessed in heparinized human whole blood within a couple of hours' incubation. Using appropriate ligands, specific subsets of lymphocytes or granulocytes are activated in this ex vivo condition to induce various mRNA, and such mRNA expression was inhibited by preincubation with kinase inhibitors in a dose dependent manner. Since the variation among triplicate aliquots of whole blood was so small that the system is capable of identifying 50% changes as significant results, and IC50 is determined in each subject. The system uses 50 microlitters of whole blood per reaction, and high throughput 96 well-format allows us to screen various compounds using blood samples from healthy donors and appropriate disease patients. ex vivo assay also identifies undesirable direct effects on leukocytes, and distinguish high- or low responders among subject's populations, which provide new insight in drug development processes toward tailored medicine.

5:30 in vivo Genetic Approaches to Identify Mechanisms of Resistance to Inhibition of ErbB-family Receptor Tyrosine Kinases
Ronan O'Hagan, Ph.D., Group Leader, Target Validation/Biology, AVEO Pharmaceuticals, Inc.
To exploit our pipeline of inducible in vivo tumor models for target identification, AVEO has developed functional genetic screens to identify novel cancer targets. These screens identify in an unbiased fashion, gene targets that can functionally drive the growth of tumors which have been engineered to contain genetic lesions relevant to human cancer, and which retain critical tumor/stromal interactions. Moreover, targets identified in RTK-driven tumor models define pathways that represent known, and novel mechanisms of acquired and de novo resistance to RTK inhibitors. As such, these proteins are potential biomarkers to identify a priori patients in which current therapies are likely to succeed or fail. In addition, targets identified in these screens represent bona-fide cancer targets in themselves, particularly in tumors with acquired drug resistance. Finally, the inducible in vivo tumor models provide unique tools in which to better understand the role of known and novel targets, and in particular to identify genetic signatures of responsive vs. non-responsive tumor populations. 

6:00 Happy Hour in the Exhibit Hall 

7:30 End of Day