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

• Published in: Journal of medicinal chemistry Vol. 59; no. 21; pp. 9942 - 9959
• Main Authors: McClure, Jesse J, Zhang, Cheng, Inks, Elizabeth S, Peterson, Yuri K, Li, Jiaying, Chou, C. James
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2016; Amer Chemical Soc
• Subjects: Allosteric Regulation - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; 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; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; CELL LUNG-CANCER; TRIAL; ORAL VORINOSTAT; SOLID TUMORS; MEMORY; SUBEROYLANILIDE HYDROXAMIC ACID; INDUCED COGNITIVE DEFICITS; PHASE-II; PIVALOYLOXYMETHYL BUTYRATE; EXPRESSION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01385

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.