Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells
Joshua P. Smalley, India M Baker, Wiktoria A. Pytel, Li‐Ying Lin, Karen J. Bowman, John W. R. Schwabe, Shaun M. Cowley, James T. Hodgkinson
Abstract
values for HDAC1 and/or HDAC3 in HCT116 cells. A hook effect was observed for HDAC3 that could be negated by modifying the position of attachment of the VHL ligand to the linker. The more potent HDAC1/2 degraders correlated with greater total differentially expressed genes and enhanced apoptosis in HCT116 cells. We demonstrate that HDAC1/2 degradation by PROTACs correlates with enhanced global gene expression and apoptosis, important for the development of more efficacious HDAC therapeutics with reduced side effects.
Topics & Concepts
ChemistryHistone deacetylaseHDAC3HDAC1CorepressorVorinostatUbiquitin ligaseEpigeneticsCell biologyBiochemistryHistoneUbiquitinBiologyTranscription factorGeneNuclear receptorProtein Degradation and InhibitorsHistone Deacetylase Inhibitors ResearchUbiquitin and proteasome pathways