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bioRxiv · 10.1101/2025.08.16.670669

Structural rationalization of IPMK inhibitor potency.

Wang, H.·Shears, S. B.·Blind, R. D.
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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. Here, we report 14 novel co-crystal structures (1.7[A] - 2.0[A] 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 KD 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 molecular basis for observed increases in potency and selectivity, the data presented here provide a toolbelt of 14 novel inhibitor-bound structures of human IPMK that can serve as a reference for all future IPMK structure-based inhibitor development efforts.

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Wang, H., Shears, S. B., Blind, R. D.. 2025-08-16. Structural rationalization of IPMK inhibitor potency.. https://doi.org/10.1101/2025.08.16.670669

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