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第3日 : 6月25日

8:15am Continental Breakfast-with-the-Experts: Breakout Roundtable Discussions

Table 1: Doriano Fabbro Ph.D., Head of Kinase Biology & Technologies, Expertise Platform Kinases, Novartis Institutes of BioMedical Research
Multi-Targeted vs Selective Kinase Inhibitors: 乬To be Safe or Not to be Safe乭

Table 2: Doris Hafenbradl, Ph.D., Executive Vice President, Screening & Proteins, Proteros Biostructures
Drug-Kinase Binding Kinetics

Table 3: Rob Bradbury, Ph.D., Principal Scientist, Cancer and Infection Research, AstraZeneca
Screening Compound Collections for Kinase Inhibitors - Focused, Subset or HTS?

Table 4:  John Doukas, Ph.D., Senior Director, Pharmacology, TargeGen, Inc.
Maximizing the Therapeutic Index

Table 5:  Potential Roles for Companion Diagnostics in Clinical Development and Use of Therapeutic Protein Kinase Inhibitors
Stephen K. Burley, Ph.D., D. phil., F.R.S.C., Chief Scientific Officer and Senior Vice President, Research, SGX Pharmaceuticals, Inc.

Expanding the Therapeutic Scope – Beyond Cancer

9:15 Kinase Inhibitors for the Treatment of Inflammatory Diseases
John Doukas, Ph.D., Senior Director, Pharmacology, TargeGen, Inc.
Inflammation drives the development of many diseases, however the specific pattern of cells and cytokines involved can differ greatly between indications. Intervention at the level of intracellular signaling kinases represents a logical approach to this diversity, as multiple biological mediators can signal through a single common pathway, and therefore blocking one pathway can inhibit across a range of responses. We have focused on two such kinases, phosphoinositide 3-kinase (PI3K) and Janus kinase (JAK), developing specific small molecule inhibitors and then applying these to animal models of inflammatory diseases. For example, using asthma as an example of a Th3-driven allergic hypersensitivity response, we have significantly reduced pulmonary inflammation and airway constriction using aerosolized PI3K inhibitors delivered via an inhalation route. Using rheumatoid arthritis as an example of a Th1-driven autoimmune disease, we have also dramatically inhibited disease progression using orally-delivered JAK inhibitors.

9:45 Networking Coffee Break

10:15  Cell Cycle-Specific Regulation of Nucleotide Excision Repair in Human Cells
Elliot Drobetsky, Ph.D., Associate Professor, Faculty of Medicine, University of Montreal; Directeur, Axe de Recherche en Immunologie/Oncologie, Centre de Recherche, Hôpital Maisonneuve-Rosemont
Nucleotide excision repair (NER) is the only  pathway available to humans for removing highly-genotoxic helix-distorting DNA lesions induced by a multitude of environmental carcinogens (eg., ultraviolet light) as well as by certain widely-employed chemotherapeutic drugs (eg., cisplatin). Recently my laboratory developed a sensitive, flow cytometry-based assay which has permitted, for the first time, the precise evaluation of NER efficiency as a function of cell cycle. The exploitation of this assay to reveal highly-novel mechanistic insights into the human NER process, and the attendant implications for cancer development and treatment, will be discussed.

10:45 Technology Watch (Sponsorship Available)

11:15 Structure-Based p70 S6 Kinase Inhibitor Design
Faming Zhang, Ph.D., Associate Professor, Chemistry, Indiana University & Crown Bioscience
Ribosomal s6 kinase 1 has been indicated as a target for obesity and insulin resistance, it is also been linked to some tumor models. The crystal structure of the kinase domain complexed with some inhibitors will be reported.

11:45 Luncheon Workshop (Sponsorship Available) or Lunch on Your Own

Structure-Based Design

Featured Presentation
1:15pm High-Throughput Crystallography of Protein Kinases as a Tool for Drug Discovery
Stefan Knapp, Ph.D., Principal Investigator, Phosphorylation Dependent Signalling Group, Structural Genomics Consortium, Oxford University, UK
Recently protein family targeted structural genomics has significantly increased the structural coverage of the human proteome. In the kinase area, our laboratory released more than 30 novel catalytic domain structures in addition to a large number of kinase inhibitor complexes during the past three years. These efforts lead to a significantly improved structural coverage of the human kinome. In addition, many representative structures for disease related kinases were determined where previously only structures of distantly related kinases were publicly available.

1:45 Crystal Structure of Plk-1 Solved Using a Selective DARPin
Roman Hillig, Ph.D., Scientist, Structural Biology/Lead Discovery, Bayer Schering Pharma AG
The kinase domain of Plk-1 turned out to be a challenging crystallization target. After all conventional crystallization screens had failed, we generated selective designed ankyrin repeat proteins (DARPins) and used them in co-crystallization screens. This approach finally yielded crystals which allowed structure determination and structure-based drug design.

2:15 Speaker to be Announced

2:45 Networking Refreshment Break

3:15  Utilizing Protein Conformational Flexibility in Drug Design: A Case Study in Kinases
Glenn Noronha, Ph.D., Director of Chemistry, TargeGen, Inc.
We describe the development of highly potent kinase inhibitors against SRC, VEGFr, ABL, and ABL-T315I. The inhibitors were designed by a structure-guided approach using target flexibility by building models of conformations of the proteins not seen in previous crystal structures. Series of compounds described here show single digit nanomolar inhibition, one of which is currently in clinical trials. The approach demonstrates the critical nature of introducing an interaction with a single highly-conserved glutamate on the C-helix that plays a pivotal role in kinase activation

3:45  Targeting Multiple Conformations of Protein Kinases for the Design of Small-Molecule Inhibitors
Jeffrey Liao, Ph.D., TransTech Pharma, Inc.
Multiple conformations of a protein kinase target offer an opportunity to design small-molecule inhibitors with distinct but clinically useful profiles. In this talk, classification of the binding pockets in the kinase catalytic cleft in different conformational states will be provided. Targeting kinase multiple conformations as an emerging strategy in the field is exemplified with important small-molecule agents in the clinic. The structure-based analysis provides a rationale for thwarting the development of drug-resistant mutations in anti-kinase therapy.

4:15 Fragment Discovery and Characterization for a priori Selection of Mode of Action of Kinase Inhibitors
Gregg Siegal, Ph.D., CSO, ZoBio, The Netherlands
Fragment based drug discovery has significant advantages in generating novel, protectable compounds with good PK properties, yet traditionally requires large quantities of protein and is resource intensive, especially when applied to kinases. We have developed a technology called TINS (Target Immobilized NMR Screening) that makes highly efficient use of a single sample (few mg乫s) of protein to rapidly screen our innovative fragment library. TINS has been used to selectively screen activated and non-activated kinases. Hits from TINS can be rapidly assayed for biologically activity, including ATP competition, using a proprietary solid phase technology. In this way structural studies can be carried out on a focus set of highly characterized fragments exhibiting the desired mode of action. Examples of our combination of hit discovery and characterization will be provided.

4:45 End of Conference

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