Optimization of Class I Histone Deacetylase JPS0s Reveals HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells

Class I Histone Deacetylase (HDAC) enzymes 1, 2 & 3 organize chromatin as the catalytic subunits within seven distinct multi-protein co-repressor complexes and are established drug targets. We report optimization studies of benzamide based Von Hippel-Lindau (VHL) E3-ligase Proteolysis Targeting Chimeras (JPS0s), and for the first time describe transcriptome perturbations resulting from these degraders. By modifying the linker and VHL ligand we identified JPS0s 7, 9 & 21 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 JPS0s correlates with enhanced global gene expression and apoptosis, important for the development of more efficacious HDAC therapeutics with reduced side effects. Overall design: Determining differential gene expression profiles upon treatment of HCT116 cells with JPS0s targeting class I HDACs