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Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

ABSTRACT: Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics-single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease.

SUBMITTER: Smalley JP

PROVIDER: S-EPMC7583022 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

Smalley Joshua P JP Cowley Shaun M SM Hodgkinson James T JT

Molecules (Basel, Switzerland) 20200924 19

Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics-single molecules comprisin ...[more]

PMID: 32987782

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