In the last 15 years, 28 small molecule kinase inhibitors have been approved for various indications by the FDA. These molecules were discovered using a variety of approaches such as target-based HTS, phenotypic screening, as well as fragment and structure-based design efforts and represent a range of reversible and irreversible chemical scaffolds. While the majority of these inhibitors bind to the active conformation of the kinase (type I inhibitors), type II inhibitors, which bind to an inactive conformation, have also been found to be clinically useful. Type II inhibitors offer significant chemical diversity over the classical type I inhibitors. Through activation loop rearrangement, these inhibitors can access or even open pockets adjacent to the ATP binding site, where the amino acid sequence is less conserved, thus potentially offering greater avenues for selectivity. However, finding novel type II inhibitors can be challenging. Structure-based design methods are limited in this space until the first type II inhibitor has been found and successfully crystallized. Using known type II inhibitors for other kinases has worked in some cases, but not all. In theory, setting up an HTS campaign, using an enzyme form which can adopt multiple conformations (not just the active conformation), should increase the chances of identifying type II inhibitors. We have used such an approach and supplemented this effort with high-throughput mechanism studies to rapidly bin hits based on structure, potency, residence time and mode of inhibition for further characterization. In this way, we have identified and confirmed type II inhibitors for new kinase targets. The identification of diverse chemical scaffolds at this stage in a discovery effort provides multiple avenues for successful lead optimization.

Identifying putative type II inhibitors from HTS campaigns: Importance of high-throughput mechanism studies in the hit triage process

251st National Meeting (2016)

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