PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes
Joshua P. Smalley, Grace E. Adams, Christopher J. Millard, Yun Song, James K. S. Norris, John W. R. Schwabe, Shaun M. Cowley, James T. Hodgkinson
Abstract
We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition.
Topics & Concepts
CorepressorHistone deacetylaseAcetylationHistoneChemistryHDAC11ProteolysisEnzymeHDAC10BiochemistryCell biologyRepressorBiologyGene expressionGeneProtein Degradation and InhibitorsHistone Deacetylase Inhibitors ResearchUbiquitin and proteasome pathways