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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Mar 16

PMID 35293758

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

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