Development of
Allosteric Hydrazide-Containing Class
I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia
Jesse
J. McClure
Cheng Zhang
Elizabeth S. Inks
Yuri K. Peterson
Jiaying Li
C. James Chou
10.1021/acs.jmedchem.6b01385.s002
https://acs.figshare.com/articles/dataset/Development_of_Allosteric_Hydrazide-Containing_Class_I_Histone_Deacetylase_Inhibitors_for_Use_in_Acute_Myeloid_Leukemia/4077438
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 <i>N</i>-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.
2016-10-18 00:00:00
motif
Allosteric Hydrazide-Containing Class
HDAC inhibitors
HEK
Acute Myeloid Leukemia
Histone Deacetylase Inhibitors
AML