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
DC
50
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.
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