jm6b01385_si_002.csv (3.74 kB)
Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia
dataset
posted on 2016-10-18, 00:00 authored by Jesse
J. McClure, Cheng Zhang, Elizabeth S. Inks, Yuri K. Peterson, Jiaying Li, C. James ChouOne 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.