Identification of ARUK2002821 as an isoform-selective PI5P4Kα inhibitor

The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a central role in regulating cell signalling pathways and, as such, have become therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders. Many of the PI5P4Kα inhibitors that have been reported to date have suffered from poor selectivity and/or potency and the availability of better tool molecules would facilitate biological exploration. Herein we report a novel PI5P4Kα inhibitor chemotype that was identified through virtual screening. The series was optimised to deliver ARUK2002821 ( 36 ), a potent PI5P4Kα inhibitor (pIC 50 = 8.0) which is selective vs. other PI5P4K isoforms and has broad selectivity against lipid and protein kinases. ADMET and target engagement data are provided for this tool molecule and others in the series, as well as an X-ray structure of 36 solved in complex with its PI5P4Kα target. The PI5P4Ks play a central role in regulating cell signalling pathways. ARUK2002821 is reported as a potent and selective PI5P4Kα inhibitor (pIC 50 = 8.0). ADMET and target engagement data are provided, with a ligand-protein X-ray structure, optimised to deliver ARUK2002821.