Issue 9, 2023

PROTAC chemical probes for histone deacetylase enzymes

Abstract

Over the past three decades, we have witnessed the progression of small molecule chemical probes designed to inhibit the catalytic active site of histone deacetylase (HDAC) enzymes into FDA approved drugs. However, it is only in the past five years we have witnessed the emergence of proteolysis targeting chimeras (PROTACs) capable of promoting the proteasome mediated degradation of HDACs. This is a field still in its infancy, however given the current progress of PROTACs in clinical trials and the fact that FDA approved HDAC drugs are already in the clinic, there is significant potential in developing PROTACs to target HDACs as therapeutics. Beyond therapeutics, PROTACs also serve important applications as chemical probes to interrogate fundamental biology related to HDACs via their unique degradation mode of action. In this review, we highlight some of the key findings to date in the discovery of PROTACs targeting HDACs by HDAC class and HDAC isoenzyme, current gaps in PROTACs to target HDACs and future outlooks.

Graphical abstract: PROTAC chemical probes for histone deacetylase enzymes

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Article information

Article type
Review Article
Submitted
27 Jun 2023
Accepted
27 Jul 2023
First published
27 Jul 2023
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2023,4, 623-634

PROTAC chemical probes for histone deacetylase enzymes

U. Patel, J. P. Smalley and J. T. Hodgkinson, RSC Chem. Biol., 2023, 4, 623 DOI: 10.1039/D3CB00105A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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