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.