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- W4381738355 abstract "Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development of potent IP6K inhibitors is gaining momentum, a pharmacological tool to distinguish the mammalian isozymes is still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed a high-throughput screen to identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency and selectivity toward the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type (WT) kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by hydrogen deuterium exchange mass spectrometry measurements. The latter analysis suggested that displacement of the αC helix, caused by the gatekeeper mutation, facilitates the binding of FMP-201300 to an allosteric pocket adjacent to the ATP-binding site. FMP-201300 therefore serves as a valuable springboard for the further development of compounds that can selectively target the three mammalian IP6Ks; either as analog-sensitive kinase inhibitors or as an allosteric lead compound for the WT kinases." @default.
- W4381738355 created "2023-06-24" @default.
- W4381738355 creator A5008781299 @default.
- W4381738355 creator A5010484109 @default.
- W4381738355 creator A5010631390 @default.
- W4381738355 creator A5011797858 @default.
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- W4381738355 creator A5015683098 @default.
- W4381738355 creator A5065811086 @default.
- W4381738355 creator A5075104061 @default.
- W4381738355 creator A5088211325 @default.
- W4381738355 date "2023-10-16" @default.
- W4381738355 modified "2023-10-18" @default.
- W4381738355 title "An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor" @default.
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