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

One of the biggest hurdles yet to be overcome for the continued improvement of histone deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based...

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Published in:Journal of medicinal chemistry 2016-11, Vol.59 (21), p.9942-9959
Main Authors: McClure, Jesse J, Zhang, Cheng, Inks, Elizabeth S, Peterson, Yuri K, Li, Jiaying, Chou, C. James
Format: Article
Language:English
Subjects:
Allosteric Regulation - drug effects
Cell Line, Tumor
Cell Survival - drug effects
Dose-Response Relationship, Drug
HEK293 Cells
HeLa Cells
Histone Deacetylase Inhibitors - chemical synthesis
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - metabolism
Humans
Hydrazones - chemical synthesis
Hydrazones - chemistry
Hydrazones - pharmacology
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - metabolism
Leukocytes, Mononuclear - drug effects
Models, Molecular
Molecular Structure
Structure-Activity Relationship
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Summary:One of the biggest hurdles yet to be overcome for the continued improvement of histone deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations. With the goal of developing a second generation of HDAC inhibitors lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of our lead analogues’ efficacy, selectivity, and toxicity profiles demonstrate that they possess low nanomolar activity against models of acute myeloid leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01385