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Structural Rationalization of IPMK Inhibitor Potency.

Huanchen Wang1, Stephen B Shears1, Raymond D Blind2,3

  • 1Molecular and Cellular Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, United States.

Journal of Medicinal Chemistry
|November 14, 2025
PubMed
Summary
This summary is machine-generated.

Structural insights into potent inositol polyphosphate multikinase (IPMK) inhibitors reveal key interactions within the ATP-binding site. This study provides 14 novel structures to guide future cancer drug development targeting IPMK.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Medicinal Chemistry

Background:

  • Inositol polyphosphate multikinase (IPMK) is implicated in various cancers.
  • Targeting IPMK with ATP-competitive inhibitors shows promise for cancer therapy.
  • The structural basis for potent IPMK inhibition remains largely unexplored.

Purpose of the Study:

  • To elucidate the structural mechanisms underlying the high potency of novel IPMK inhibitors.
  • To provide a comprehensive structural reference for future IPMK inhibitor design.
  • To understand the molecular interactions driving inhibitor selectivity and efficacy.

Main Methods:

  • X-ray crystallography to determine 14 novel cocrystal structures of human IPMK kinase domain.
  • Radiolabeled assays for IC50 determination.
  • Isothermal titration calorimetry for KD value determination.

Main Results:

  • Detailed atomic resolution structures of human IPMK bound to 14 distinct inhibitors.
  • Identification of a specific pocket within the ATP-binding site crucial for high-potency inhibitor binding.
  • Observation of two ordered water molecules contributing to hydrogen-bonding networks with potent inhibitors.

Conclusions:

  • The study provides the molecular basis for the potency and selectivity of novel IPMK inhibitors.
  • The 14 novel inhibitor-bound IPMK structures serve as a valuable resource for future structure-based drug discovery efforts.
  • This work advances the development of targeted cancer therapies by illuminating IPMK-inhibitor interactions.