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

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.