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Updated: Jun 1, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Metabolism as a key to histone deacetylase inhibition
Praveen Rajendran1, David E Williams, Emily Ho
1Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
Abstract:
There is growing interest in the epigenetic mechanisms that are dysregulated in cancer and other human pathologies. Under this broad umbrella, modulators of histone deacetylase (HDAC) activity have gained interest as both cancer chemopreventive and therapeutic agents. Of the first generation, FDA-approved HDAC inhibitors to have progressed to clinical trials, vorinostat represents a "direct acting" compound with structural features suitable for docking into the HDAC pocket, whereas romidepsin can be considered a prodrug that undergoes reductive metabolism to generate the active intermediate (a zinc-binding thiol). It is now evident that other agents, including those in the human diet, can be converted by metabolism to intermediates that affect HDAC activity. Examples are cited of short-chain fatty acids, seleno-α-keto acids, small molecule thiols, mercapturic acid metabolites, indoles, and polyphenols. The findings are discussed in the context of putative endogenous HDAC inhibitors generated by intermediary metabolism (e.g. pyruvate), the yin-yang of HDAC inhibition versus HDAC activation, and the screening assays that might be most appropriate for discovery of novel HDAC inhibitors in the future.
Insights
Histone deacetylase (HDAC) inhibitors, like vorinostat and romidepsin, show promise in cancer therapy. Dietary compounds and metabolic intermediates also modulate HDAC activity, offering new avenues for drug discovery.
Area of Science:
- Epigenetics and molecular biology
- Cancer research
- Pharmacology
Background:
- Growing interest in epigenetic mechanisms dysregulated in cancer and other pathologies.
- Histone deacetylase (HDAC) inhibitors are investigated as cancer chemopreventive and therapeutic agents.
- First-generation FDA-approved HDAC inhibitors include vorinostat (direct-acting) and romidepsin (prodrug).
Purpose of the Study:
- To explore the role of dietary and metabolic compounds as HDAC modulators.
- To discuss the implications for discovering novel HDAC inhibitors.
- To contextualize HDAC inhibition within intermediary metabolism and potential activation.
Main Methods:
- Review of existing literature on HDAC inhibitors and modulators.
- Analysis of structural features of known HDAC inhibitors (vorinostat, romidepsin).
- Identification of dietary and metabolic compounds affecting HDAC activity.
Main Results:
- Vorinostat directly inhibits HDACs, while romidepsin is a prodrug metabolized to an active thiol.
- Dietary compounds like short-chain fatty acids, indoles, and polyphenols can modulate HDAC activity.
- Endogenous metabolites such as pyruvate may also act as HDAC inhibitors.
Conclusions:
- Metabolism converts various dietary and endogenous compounds into intermediates that affect HDAC activity.
- The interplay between HDAC inhibition and activation presents complex therapeutic considerations.
- Development of novel screening assays is crucial for identifying new HDAC inhibitors from diverse sources.
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