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

journal contribution
posted on 2022-03-21, 16:28 authored by Joshua P Smalley, India M Baker, Wiktoria A Pytel, Li-Ying Lin, Karen J Bowman, John WR Schwabe, Shaun M Cowley, James T Hodgkinson
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.

History

Citation

Journal of Medicinal Chemistry, 2022, https://doi.org/10.1021/acs.jmedchem.1c02179

Author affiliation

Leicester Institute of Structural and Chemical Biology, School of Chemistry

Version

  • AM (Accepted Manuscript)

Published in

Journal of Medicinal Chemistry

Publisher

American Chemical Society (ACS)

issn

0022-2623

eissn

1520-4804

Acceptance date

2022-03-08

Copyright date

2022

Available date

2023-03-16

Language

en

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