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

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.

Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia

“…The non-selective metal chelating properties of the hydroxamate are what allow it to bind the catalytic zinc metal that HDACs rely on, but also cause compounds containing these groups to be associated with many undesirable effects secondary to non-targeted active site metal chelation. 35 While all FDA approved inhibitors demonstrate very strong efficacy in the sub-micromolar range, the doses given in clinic are relatively much higher. The reason for this increased required dose, and the subsequent side effects due to off-target effects, could be in part to a metabolic inactivation of some of these compounds.…”

Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

“…In an effort to synthesize the cyclic disulfide 25, the starting material, 5-bromo-1-pentene (17), was first oxidized with m-CPBA to afford the oxirane (18, Scheme 6). Without purification, the crude product of 18 was reacted with 5,6-dichloroindole (3a) in the presence potassium hydroxide to provide 19 in good yield.…”

“…The hydroxamic acid group has in many cases proven to be genotoxic, thus leading to chromosomal aberrations, and as such represents a major hindrance for clinic development beyond oncology, especially for long-term treatments. 17 To identify more promising HDAC6 inhibitors, our group has initiated studies to develop HDAC6 selective inhibitors with a mercaptoacetamide group as the ZBG. Our previous efforts led to the discovery of MF-2−30, which is a potent and selective HDAC6 inhibitor (Figure 1).…”

OleD Loki as a Catalyst for Hydroxamate Glycosylation

“…Consistent with the prior comparison of the catalytic competencies for trichostatin A ( k cat / K M =1.4×10 4 μm −1 s −1 ) to the parental OleD Loki acceptor 4‐methylumbelliferone ( k cat / K M =2.2×10 4 μm −1 s −1 ), the current study highlights OleD Loki as an efficient and permissive biocatalyst for HDACi glucosylation as a basis for exploring glycoconjugate tumor targeting and/or prodrug strategies . Hydroxamate glycosylation is also expected to circumvent the Lossen rearrangement to a highly reactive isocyanate, a reaction known to contribute to nonspecific alkylation and corresponding off‐target toxicity observed by HDACis . Most hydroxamates also suffer from rapid metabolism and clearance, where UDP‐glucuronosyltransferase (UGT)‐catalyzed hydroxamate glucuronidation plays a major role .…”