Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity.
Basic Information
ID: ALA5126568
Journal: ACS Med Chem Lett
Title: Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity.
Authors: Moreno-Yruela C, Olsen CA.
Abstract: Histone deacetylases (HDACs) 1-3 regulate chromatin structure and gene expression. These three enzymes are targets for cancer chemotherapy and have been studied for the treatment of immune disorders and neurodegeneration, but there is a lack of selective pharmacological tool compounds to unravel their individual roles. Potent inhibitors of HDACs 1-3 often display slow-binding kinetics, which causes a delay in inhibitor-enzyme equilibration and may affect assay readout. Here we compare the potencies and selectivities of slow-binding inhibitors measured by discontinuous and continuous assays. We find that entinostat, a clinical candidate, inhibits HDACs 1-3 by a two-step slow-binding mechanism with lower potencies than previously reported. In addition, we show that RGFP966, commercialized as an HDAC3-selective probe, is a slow-binding inhibitor with inhibitor constants of 57, 31, and 13 nM against HDACs 1-3, respectively. These data highlight the need for thorough kinetic investigation in the development of selective HDAC probes.
CiteXplore: 35586419
DOI: 10.1021/acsmedchemlett.1c00702
Patent ID: ┄