An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor
Authors
- T. Aguirre
- S. Hostachy
- G.L. Dornan
- M. Neuenschwander
- C. Seyffarth
- V. Haucke
- A. Schütz
- J.P. von Kries
- D. Fiedler
Journal
- eLife
Citation
- eLife 21: RP88982
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 towards the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by HDX-MS 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 wild-type kinases.