A Cysteine Unique to Pyk2 Lets a Covalent Inhibitor Spare Its Sister Kinase FAK1
- Preprint, not yet peer reviewed: the team starts from a reversible Pyk2 inhibitor and, guided by structure, adds an acrylamide warhead and a methylazetidine linker to reach a cysteine that FAK1 lacks.
- Cellular target-engagement assays and an alkyne-tagged probe support covalent binding and a clean kinome-wide selectivity profile.
- In platelets it blunted thromboxane-analog responses with little effect on ADP and thrombin pathways, and cut adhesion under simulated flow about as much as aspirin.
- In a carotid artery thrombosis model it boosted tPA's clot-dissolving effect without added bleeding.
💡 Points Based on the abstract
One non-conserved cysteine looks like a thin basis for selectivity, yet an acrylamide on an azetidine linker reaching Cys545 is a clean way to tell paralogs apart, and the alkyne probe with kinome profiling suggests the warhead is not simply promiscuous. Still open: GSH reactivity, protein turnover for a platelet target, and how this stacks up against reversible FAK/Pyk2 chemotypes.