2. Academic Validation
  3. Design, Synthesis, and Cellular Characterization of a New Class of IPMK Kinase Inhibitors

Design, Synthesis, and Cellular Characterization of a New Class of IPMK Kinase Inhibitors

  • J Med Chem. 2025 Aug 14;68(15):15446-15460. doi: 10.1021/acs.jmedchem.5c00015.
Yubai Zhou 1,  Pratima Chapagain 2 3,  Desmarini Desmarini 4 5,  Dilipkumar Uredi 1,  Michael A Stashko 1,  Hundaol Huluka 2 3,  Lucia E Rameh 2 6,  Julianne T Djordjevic 4 5,  Raymond D Blind 2 3,  Xiaodong Wang 1 7
Affiliations

Affiliations

  • 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 3 Departments of Biochemistry & Pharmacology, Vanderbilt University School of Medicine, Nashville Tennessee 37232, United States.
  • 4 Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Westmead NSW 2145, Australia.
  • 5 Sydney Institute for Infectious Diseases, Faculty of Medicine and Health, University of Sydney, Sydney NSW 2006, Australia.
  • 6 Department of Biochemistry & Molecular Biology, University of South Alabama, Mobile, Alabama 36688, United States.
  • 7 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 40709844 DOI: 10.1021/acs.jmedchem.5c00015
Abstract

The kinase activity of human inositol phosphate multikinase (IPMK) is required for the synthesis of higher-order inositol phosphate signaling molecules, regulation of gene expression, and control of the cell cycle. Here, we report a novel series of highly potent IPMK inhibitors. The first-generation IPMK inhibitor 1 (UNC7437) decreased cellular proliferation and tritiated inositol phosphate levels in metabolically labeled human U251-MG glioblastoma cells. It also impacted the transcriptome of these cells, selectively regulating 993 genes enriched in Cancer, epithelial-to-mesenchymal transition (EMT), and inflammatory and viral Infection pathways, consistent with Anticancer growth activity. Extensive optimization of 1 led to 14 (UNC9750) with improved pharmacokinetic properties. Compound 14 inhibited cellular accumulation of InsP5, the direct product of IPMK kinase activity, while having no effect on either InsP6 or InsP7 levels. These studies suggest that rapid chemical inhibition of IPMK induces a novel InsP5 metabolic signature, providing new biological insights into inositol phosphate metabolism and signaling.

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