Protein kinases constitute one of the largest protein families with over 500 members, and are involved in many critical cellular processes and signaling pathways. Due to the important roles kinases play in biological processes they have been heavily pursued as therapeutic targets, especially in oncology and inflammation. One of the major concerns for kinase targets is selectivity over other kinases since most small molecule kinase inhibitors bind to the highly conserved ATP binding site. The most common approach to achieve selectivity is to identify sequence differences in the binding site and incorporate designs to insult the off-targets while maintaining potency against the target. In this presentation I will show you several examples where we have exploited both the obvious (sequence-based) and nonobvious features (structural plasticity and pharmacophore manipulation) to achieve either broad kinase selectivity or selectivity over closely related kinases.

Design strategies for selective kinase inhibitors: Classical and non-classical approaches

254th National Meeting (2017)

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