7qie

Publication Abstract from PubMed

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 PI5P4Kgamma inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4Kgamma in intact cells and that compounds from this series do not inhibit PI5P4Kalpha or PI5P4Kbeta. Furthermore, the first X-ray structure of PI5P4Kgamma 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 A from the ATP pocket.

Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase gamma Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.,Boffey HK, Rooney TPC, Willems HMG, Edwards S, Green C, Howard T, Ogg D, Romero T, Scott DE, Winpenny D, Duce J, Skidmore J, Clarke JH, Andrews SP J Med Chem. 2022 Feb 24;65(4):3359-3370. doi: 10.1021/acs.jmedchem.1c01819. Epub , 2022 Feb 11. PMID:35148092^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.