Wednesday, June 14th*
Pre-Conference Short Course:

Designing Structure-Based Kinase Inhibitors
Dedicated Focus on Computational Kinase

12:30pm Pre-Conference Registration

1:40 Chairperson’s Opening Remarks

1:45 Selectivity of Kinase Inhibitors
Dr. Doris Hafenbradl, Director Biochemical Screening, GPC Biotech, Germany
This presentation will address different tools and technologies for the determination
of kinase inhibitor selectivity. It will be shown how critical it is to evaluate selectivity with suitable data. The structural aspects of protein kinases determining the selectivity will also be highlighted. It will be discussed how selectivity data can be used within the lead finding and optimization processes.

2:15 Determinants of Selectivity in Targeting the JAK Family of Kinases for Treatment of Cancer and Inflammatory Disease
Dr. Andrew Wilks, Corporate Scientific Officer, R&D, Cytopia Research Pty, Ltd.,
Australia
The JAK family of PTKs has four members in the human genome (JAK1, JAK2, JAK3 and TYK2) each of which plays an important role in the intracellular signaling downstream of particular cytokines. A single point mutation in the kinase like domain of JAK2 has recently been linked to a significant proportion of cases of Myeloproliferative Disorders, including Polycythemia Vera (PCV) and Essential Thrombocytemia. Parallel computational approaches to molecular modeling, drug design and in silico screening are being explored to generate potent and highly specific small molecule inhibitors of a number of the JAK family of PTKs. Co-crystallography of these potent and specific JAK inhibitors with the JAK2 kinase domain provides important insights into the feasibility of generating drugs against these important targets.

2:45 Refreshment Break

3:15 In silico ADMET Traffic Lights and PhysChem Scores and their Application to Kinase Inhibitors
Dr. Mario Lobell, Computational Chemistry, Bayer HealthCare, Germany
The need for in silico characterization of HTS hit structures as part of a data driven hit selection process is demonstrated. A solution is described in form of the in silico ADMET Traffic Light and PhysChem scoring system. The described in silico system has been extensively validated with Bayer in-house data, literature data and a collection of launched small molecule drugs. The system is applied to examples of kinase inhibitor drugs and drug candidates.

3:45 Structural Basis for the Non-Competitive Inhibition of Human MEK1
Dr. Jeffrey Ohren, Senior Scientist, Structural Biology Group, Department of Chemistry, Pfizer Global Research & Development
MAP kinase 1 (MEK1) plays an integral role in the formation, progression and survival of tumors, in addition to mediating many inflammatory processes. As a result, MEK1 represents an attractive target for pharmacological intervention in both proliferative and inflammatory diseases. The recent X-ray structure of human MEK1 in a complex with ATP and a non-competitive, small molecule inhibitor provides structural insight into a unique mode of kinase inhibition and may provide a platform for the structure-based design of the next generation of protein kinase inhibitors.

4:15 Insights for Design: Differential Binding of Inhibitors to Active and Inactive CDK2
Dr. Campbell McInnes, Head, Structure-Based Drug Group, Cyclacel Ltd., Scotland
The cyclin-dependent kinases (CDKs) are important anti-cancer targets and despite having been characterized in complex with a wide variety of inhibitors, the majority of CDK2 structures solved are of the inactive enzyme. Crystallographic data exists for only one ATP-competitive inhibitor in both the active cyclin-bound and inactive CDK2 forms. We have solved the structures of six inhibitors in both the monomeric CDK2 and binary CDK2/cyclin A complexes and demonstrate for the first time that significant differences in binding of CDK2 ligands occur depending on the activation state. The binding mode of two ligands varies substantially as a result of binding site differences induced upon CDK2 activation. Furthermore, an energetic analysis of CDK2/cyclin complexes demonstrates that a good correlation exists between the in vitro potency and calculated energies of interaction, while
indicating that no such relationship exists for monomeric CDK2-inhibitor structures. These results confirm that structures solved in complex with the monomeric CDK2 do not fully reflect the active conformation of bound inhibitors. This analysis reveals significant implications for inhibitor design towards active structures since these are distinct from the inactive CDK2 and also suggests that the monomeric CDK2 conformation could be selectively inhibited.

4:45 End of Short Course

4:45-5:30 Main Conference Early Registration

* Separate Registration Required

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Shelley W. Amster, Conference Director
781-972-5473 • samster@healthtech.com

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781-972-5452 • scarroll@healthtech.com