8V6W

Crystal structure of the core catalytic domain of human inositol phosphate multikinase in complex with compound 1

Summary for 8V6W

• Entry DOI: 10.2210/pdb8v6w/pdb
• Descriptor: Inositol polyphosphate multikinase, (2E)-3-[3-(3,5-dimethylphenyl)-2,1-benzoxazol-5-yl]prop-2-enoic acid (3 entities in total)
• Functional Keywords: structure-based inhibitor development, kinase, inhibitor, inositol polyphosphate, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 30121.23

Authors

Wang, H.,Shears, S.B. (deposition date: 2023-12-04, release date: 2024-12-11, Last modification date: 2025-12-10)

Primary citation

Wang, H.,Shears, S.B.,Blind, R.D.
Structural Rationalization of IPMK Inhibitor Potency.
J.Med.Chem., 68:24316-24325, 2025

PubMed 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 IC and 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.

PubMed: 41237254
DOI: 10.1021/acs.jmedchem.5c02314

Experimental method

X-RAY DIFFRACTION (1.95 Å)