Insights into the modular design of kinase inhibitors and application to Abl and Axl

Scaffold hopping is a common strategy for generating kinase inhibitors that bind to the DFG-out inactive conformation. Small structural differences in inhibitor scaffolds can have significant effects on potency and selectivity across the kinome, however, these effects are often not studied in detail. Herein, we outline a design strategy to generate an array of DFG-out conformation inhibitors with three different hinge-binders and two DFG-pocket groups. We studied inhibitor selectivity across a large segment of the kinome and elucidated binding preferences that can be used in scaffold hopping campaigns. Using these analyses, we identified two selective inhibitors that display low nanomolar potency against Axl or wild-type and clinically relevant mutants of Abl.

Automated summary

The study presents a design strategy to generate a combination of kinase inhibitors with different hinge-binders and DFG-pocket groups, and investigates their selectivity. Through analysis, two selective inhibitors with low nanomolar potency against Axl or clinically relevant mutants of Abl were identified.