8bq4

Publication Abstract from PubMed

Owing to their central role in regulating cell signaling pathways, the phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive therapeutic targets in diseases such as cancer, neurodegeneration, and immunological disorders. Until now, tool molecules for these kinases have been either limited in potency or isoform selectivity, which has hampered further investigation of biology and drug development. Herein we describe the virtual screening workflow which identified a series of thienylpyrimidines as PI5P4Kgamma-selective inhibitors, as well as the medicinal chemistry optimization of this chemotype, to provide potent and selective tool molecules for further use. In vivo pharmacokinetics data are presented for exemplar tool molecules, along with an X-ray structure for ARUK2001607 (15) in complex with PI5P4Kgamma, along with its selectivity data against >150 kinases and a Cerep safety panel.

The Identification of Potent, Selective, and Brain Penetrant PI5P4Kgamma Inhibitors as In Vivo-Ready Tool Molecules.,Rooney TPC, Aldred GG, Boffey HK, Willems HMG, Edwards S, Chawner SJ, Scott DE, Green C, Winpenny D, Skidmore J, Clarke JH, Andrews SP J Med Chem. 2022 Dec 14. doi: 10.1021/acs.jmedchem.2c01693. PMID:36516442^[1]

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