Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase gamma Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode

摘要

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4K gamma inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4K gamma in intact cells and that compounds from this series do not inhibit PI5P4K alpha or PI5P4K beta. Furthermore, the first X-ray structure of PI5P4K gamma bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 angstrom from the ATP pocket.