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

Sida Shen, Alan P. Kozikowski

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Pages (from-to)15-21
Number of pages7
JournalChemMedChem
Volume11
Issue number1
DOIs
StatePublished - Jan 5 2016

Keywords

  • Lossen rearrangement
  • histone deacetylase inhibitors
  • hydroxamate
  • mutagenicity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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