Structural Rationalization of IPMK Inhibitor Potency.

ABSTRACT: Inositol polyphosphate multikinase (IPMK) is a kinase linked to several cancers; recent development of a large panel of ATP-competitive inhibitors has reinvigorated enthusiasm for targeting IPMK. However, the structural basis for how these inhibitors achieve high potency is unknown. Herein, we report 14 novel cocrystal structures (1.7-2.0 resolution) of human IPMK kinase domain with these inhibitors. We also apply a radiolabeled assay and isothermal titration calorimetry that permit high-confidence IC₅₀ and K_D value determinations. The structures reveal a pocket in the ATP-binding site engaged by the most potent inhibitors. Two ordered waters also participate in hydrogen-bonding networks associated with the most potent inhibitors. In addition to providing the m

SUBMITTER: Wang H 

PROVIDER: S-EPMC12670395 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature