The Challenge of Developing Kinase Inhibitors

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Kinase Inhibitors as drug targets are currently at the peak of research and development. New screening platforms and libraries are available - but new challenges for the industry have evolved.

What is it that the kinase community is currently struggling with? What are the top challenges that need to be addressed in a focused assembly of knowledgeable leaders in the field?  Answers to these and many other questions will be covered in this conference.


12:30 - 1:30 pm Conference Registration


Kinase Inhibitor Chemistry

1:30 Chairperson’s Remarks

Roger S. Armen, Ph.D., Assistant Professor, Department of Pharmaceutical Sciences, Thomas Jefferson University

1:40 Scaffold-Based Inhibitor Design Strategies Targeting Type II and Allosteric Sites: Future Beyond the Kinase Domain

Hariprasad Vakayalapati, M. Pharm., Ph.D., Chief Scientist, Medicinal Chemistry, Center for Investigational Therapeutics, Huntsman Cancer Institute

Finding selective protein kinase inhibitors by targeting ATP binding site is one of the major difficulties due to the significant homology
exist within the substrate binding site.The recently published crystal structure complexes revealed that the binding sites beyond the ATPbinding site termed as Type II hydrophobic site. Whereas the inactive conformation of DFG motif of Type II site extends out further creating additional hydrophobic site referred as allosteric site. Targeting Type II and allosteric sites could possibly achieve greater selectivity due to the non-conserved amino acid residue pocket representing these two sites. Scaffold-Based design approaches together with virtual ligand screening methods will be presented with our success in finding conformational specific small-molecule kinase inhibitors.

2:10 Fragments and Drug Discovery for Kinase Targets

Roderick E. Hubbard, Ph.D., Senior Fellow, Research, Vernalis, Ltd.

Over the past six years, we have used fragment and structure-based methods to discover and optimise hit and lead series against a number of kinase targets. I will review some of the lessons learnt in projects that have resulted in clinical candidates (chk1), tools to probe the biology of the target (PDPK1), or interesting phenomena in ligand binding (chk1 and cdk2). In addition, I will review issues of selectivity, binding affinity of fragments, non-ATP site binding and observations on attempting to triage the very high hit rates observed (more than 100 hits).

2:40 Scaffold Hopping as a Method to Diversify and Generate New Leads for p38

Kristofer Moffett, Ph.D., Senior Scientist, Chemistry, Ansaris, a division of Locus Pharmaceuticals, Inc.

Initial efforts to find a small molecule inhibitor of p38 relied on our proprietary computational fragment-based drug design (FBDD) technology to identify a novel fragment that we developed into a lead series and eventually into a pre-clinical candidate. This presentation will briefly cover our effort to “hop,” in increasingly larger jumps, to new scaffolds in order to diversify and create novel chemical entities while maintaining potency and selectivity for p38.

3:10 Networking Refreshment Break in the Exhibit Hall
**Drop off a business card at CHI’s Sales Booth in the Exhibit Hall for a chance to win an iPod®!

3:45 Computational Prediction of Kinase Inhibitor Selectivity for On and Off Targets

Roger S. Armen, Ph.D., Assistant Professor, Department of Pharmaceutical Sciences, Thomas Jefferson University

Computational profiling to predict kinase inhibitor selectivity can be used to incorporate the requirements of selectivity as a first initial step of the inhibitor design process. Our approach to this problem is a combination of homology modeling, CHARMM-based molecular docking and free energy calculations. Preliminary results for predicting the selectivity of 9 diverse kinase inhibitors against a panel of 105 human kinases demonstrate a reasonable predictive power for the identification of on and off targets.

4:15 The Importance of Assessing Binding Kinetics in Kinase Inhibitor Design

Yogesh Sabnis, Ph.D., Computational Chemist, Pfizer Ltd.

A number of recent publications and reviews have advocated the importance of binding kinetics and residence time in drug discovery.  Compounds that stay bound to receptors or enzymes for a longer time exhibit slow off-set kinetics and longer residence times thereby giving rise to better in vivo pharmacological effects.  Generally a pharmacological interaction of a drug with its target occurs over time and as a result, kinetics play a pervasive role from HTS to lead optimization.  By not considering time parameters, there is a potential to overlook high-value, slow-binding drug candidates.  The slower the association rates and the lower the tested concentration, the greater the length of time required to achieve equilibrium binding.  This talk will highlight a simple assay methodology to address this topic and many of the ‘inhalation by design' principles which are aimed at delivering sustained lung efficacy for inhaled medicines, whilst minimising systemic exposure.

4:45 Expert Panel Discussion: How much of a Challenge is the Selectivity of Kinase Inhibitors?

Moderator: Roger S. Armen, Ph.D., Assistant Professor, Department of Pharmaceutical Sciences, Thomas Jefferson University

5:45 End of Day

**Apple® is not a sponsor or participant in the program.

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