Resolving the deceptive isoform and complex selectivity of HDAC1/2 inhibitors. Issue 7 (21st July 2022)

• Record Type: Journal Article
• Authors: Payne, N. Connor; Mazitschek, Ralph
• Is Part Of: Cell chemical biology. Volume 29:Issue 7(2022)
• Page Start: 1140
• Page End: 1152.e5
• Publication Date: 2022-07-21
• Subjects: histone deacetylases -- HDAC -- corepressor complexes -- isoform selectivity -- complex selectivity -- epigenetics -- TR-FRET -- small molecules -- molecular glue -- mode of inhibition; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.03.002
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: The histone deacetylase paralogs HDAC1/2/3 and their corepressor complexes serve as epigenetic master regulators of chromatin function. Over the past decades, HDACs have been widely pursued as pharmacological targets, and considerable efforts have been invested in the development of small molecule drugs. Specifically, ortho -aminoanilide-derived inhibitors, including CI-994 and Cpd-60, stand out with their attractive selectivity profiles and have been used extensively as tools to delineate the biological roles of specific HDAC isoforms and complexes. Here, we apply a suite of activity-independent strategies to investigate how dynamic processes that regulate HDAC complexes govern the isoform and complex selectivity of HDAC inhibitors. Importantly, we find that overreliance on static and simplified biochemical activity assays has confounded the determination of the biological selectivity of these ligands. Our data urge a comprehensive reinterpretation of numerous studies utilizing these tool compounds for the interrogation of epigenetic and other cellular processes. Graphical abstract: Highlights: Dynamics of HDAC corepressor complexes govern HDAC inhibitor (HDACi) potency and isoform selectivity HDACis and inositol phosphates stabilize HDAC corepressor complexes Benzamide-bound HDACs associate into tightly inhibited corepressor complexes TR-FRET enables context-dependent and quantitative characterization of HDACis Abstract : Supported by quantitative, activity-independent TR-FRET assay platforms, Payne and Mazitschek reveal the interdependence of HDAC inhibitor activity and HDAC complex stability. The study establishes a mechanistic understanding of the previously unrecognized role that dynamic cellular processes play in governing the isoform and corepressor complex selectivity of HDAC inhibitors.