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

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 7, 9, and 22 with submicromolar
DC50 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.