PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes

We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell via...

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Bibliographic Details
Published in:Chemical communications (Cambridge, England) England), 2020-04, Vol.56 (32), p.4476-4479
Main Authors: Smalley, Joshua P, Adams, Grace E, Millard, Christopher J, Song, Yun, Norris, James K. S, Schwabe, John W. R, Cowley, Shaun Michael, Hodgkinson, James T
Format: Article
Language:English
Subjects:
Acetylation
Animals
Antineoplastic Agents - pharmacology
Benzamide
Cell Line, Tumor
Cell Survival - drug effects
Co-Repressor Proteins - metabolism
Colon
Degradation
Histone Deacetylase 1 - antagonists & inhibitors
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - metabolism
Histone Demethylases - antagonists & inhibitors
Histones
Humans
Mice
NMR
Nuclear magnetic resonance
Proteolysis
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Summary:We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition. We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. Our PROTAC decreased HDAC 1, 2 & 3 protein abundance, increased histone acetylation levels and compromised colon cancer HCT116 cell viability.
ISSN:1359-7345
1364-548X
DOI:10.1039/d0cc01485k