title: Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia.
abstract: 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.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina , Charleston, South Carolina, 280 Calhoun Stret, MSC140 QF307, 29425, United States.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: McClure
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina , Charleston, South Carolina, 280 Calhoun Stret, MSC140 QF307, 29425, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina , Charleston, South Carolina, 280 Calhoun Stret, MSC140 QF307, 29425, United States.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Inks
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina , Charleston, South Carolina, 280 Calhoun Stret, MSC140 QF307, 29425, United States.
authors.forename: Yuri K
authors.initials: YK
authors.lastname: Peterson
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina , Charleston, South Carolina, 280 Calhoun Stret, MSC140 QF307, 29425, United States.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina , Charleston, South Carolina, 280 Calhoun Stret, MSC140 QF307, 29425, United States.
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D006835:Hydrazones; D006655:Histone Deacetylases