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

High Resolution Image Download MS PowerPoint Slide 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 InsP 5, the direct product of IPMK kinase activity, while having no effect on either InsP 6 or InsP 7 levels. These studies suggest that rapid chemical inhibition of IPMK induces a novel InsP 5 metabolic signature, providing new biological insights into inositol phosphate metabolism and signaling.