Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells

• Published in: Journal of medicinal chemistry Vol. 65; no. 7; pp. 5642 - 5659
• Main Authors: Smalley, Joshua P, Baker, India M, Pytel, Wiktoria A, Lin, Li-Ying, Bowman, Karen J, Schwabe, John W R, Cowley, Shaun M, Hodgkinson, James T
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.04.2022
• Subjects: Apoptosis; Chimera - metabolism; Histone Deacetylase 1 - metabolism; Histone Deacetylases - metabolism; Humans; Ligands; Neoplasms - drug therapy; Proteolysis; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c02179

Class I histone deacetylase (HDAC) enzymes 1, 2, and 3 organize chromatin as the catalytic subunits within seven distinct multiprotein corepressor complexes and are established drug targets. We report optimization studies of benzamide-based Von Hippel-Lindau (VHL) E3-ligase proteolysis targeting chimeras (PROTACs) and for the first time describe transcriptome perturbations resulting from these degraders. By modifying the linker and VHL ligand, we identified PROTACs , , and with submicromolar DC 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.