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Cited by 288Histone Deacetylase Inhibitors ResearchEnzyme function and inhibitionChemical Reaction Mechanisms

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

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Shen, Sida, Kozikowski, Alan P.·2016·ChemMedChem
DOI 10.1002/cmdc.201500486PMC PMC4765907
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Abstract

Hydroxamate‐based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that “pan‐HDAC inhibitors” may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate‐containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high‐potency HDACIs, is not necessarily the best zinc‐binding group for HDACI drug discovery.

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  • A major drawback of hydroxamates is poor PKs due to rapid elimination and metabolite cytotoxicity, decreasing their potential for clinical use.

    “Another major drawback to hydroxamates is their poor PKs due to rapid elimination and metabolite cytotoxicity, thus decreasing their potential for clinical use [40].”

    From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [40]

    The Introduction reports poor pharmacokinetics, specifically rapid clearance, and dose-limiting toxicity concerns for approved hydroxamate HDAC inhibitors. The Mutagenicity section discusses potentially mutagenic products of hydroxamate reactions, but does not establish metabolite cytotoxicity as the cause of poor pharmacokinetics or reduced clinical potential. The paper also notes that several such inhibitors are approved for oncology use. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Shen, S., & Kozikowski, A. P.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Kozikowski, Alan P.
ORCID
Venue
ChemMedChem
Publisher
Wiley
Published
2015-11-25
Volume
11
Issue
1
Pages
15-21
ISSN
  • 1860-7179 (ISSN-L)
  • 1860-7187
DOI
10.1002/cmdc.201500486
PMC
PMC4765907
OpenAlex
W2179490146
Cited by
288
References
6
Citations by year
2026: 35 · 2025: 42 · 2024: 45 · 2023: 34 · 2022: 25 · 2021: 28 · 2020: 24 · 2019: 23 · 2018: 15 · 2017: 8 · 2016: 9
FWCI
4.92
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • ChemMedChem (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (NS079183)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
Keywords
hydroxamate, histone deacetylase inhibitors, mutagenicity, genotoxicity, zinc-binding groups, drug toxicity
MeSH terms
Histone Deacetylases, Humans, Hydroxamic Acids, Molecular Structure, Drug Discovery, Histone Deacetylase Inhibitors

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