Christopher J Zerio, Jared Sivinski, E M Kithsiri Wijeratne, Ya-Ming Xu, Duc T Ngo, Andrew J Ambrose, Luis Villa-Celis, Niloofar Ghadirian, Michael W Clarkson, Donna D Zhang, Nancy C Horton, A A Leslie Gunatilaka, Raimund Fromme, Eli Chapman
A pulldown using a biotinylated natural product of interest in the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), identified the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, and BRD4), readers of acetyl-lysine modifications and regulators of gene transcription, as potential cellular targets. BROMOscan bromodomain profiling and biochemical assays support PCC as a BET inhibitor with increased selectivity for bromodomain (BD)-1 of BRD3 and BRD4, and X-ray crystallography and NMR studies uncovered specific contacts that underlie the potency and selectivity of PCC toward BRD3-BD1 over BRD3-BD2...
December 28, 2022: Journal of Medicinal Chemistry