Discovery of 1-hydroxypyridine-2-thiones as selective histone deacetylase inhibitors and their potential application for treating leukemia.
Histone deacetylase (HDAC) is a validated target for pursuing anticancer agents. However, obtaining a selective inhibitor against a given HDAC member remains a significant challenge. We report here the use of 1-hydroxypyridine-2-thione (1HPT) as a key pharmacophore for zinc-binding can result in highly selective HDAC inhibitors. 1HPT-6-carboxylic acid exhibits selective inhibition of HDAC6 with an IC50 of 150 nM that corresponds to a remarkable 0.9 ligand efficiency. Two analogs with simple amino acids shows nearly 600-fold selectivity among the eleven zinc-dependent HDACs. At low micromolar concentration these compounds inhibit the growth of HDAC8-overexpressing chronic myelogenous leukemia cells and specific form of acute myelogenous leukemia cells. Their potential mode of binding was examined by molecular docking and their stability was assessed in mouse and human plasma. Together the results suggest 1HPT analogs exhibit promising therapeutic potential for further development as anticancer agents to treat leukemia.
Center for Orphan Drug Research, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States; Department of Experimental & Clinical Pharmacology, University of Minnesota, 717 Delaware St SE, Minneapolis, MN 55455, United States. Electronic address: muthy003@umn.edu.
Ramaiah
R
Muthyala
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States; Biomedical Informatics and Computational Biology Program, United States.
Woo Shik
WS
Shin
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States.
Jiashu
J
Xie
Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States; Biomedical Informatics and Computational Biology Program, United States. Electronic address: shamx002@umn.edu.
Yuk Yin
YY
Sham
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D013871:Thiones; C008704:pyrithione; D006655:Histone Deacetylases
Drug resistance; HDAC; Leukemia; Pyrithione; Thiohydroxamic acid