2. Academic Validation
  3. Discovery of 1-hydroxypyridine-2-thiones as selective histone deacetylase inhibitors and their potential application for treating leukemia

Discovery of 1-hydroxypyridine-2-thiones as selective histone deacetylase inhibitors and their potential application for treating leukemia

  • Bioorg Med Chem Lett. 2015 Oct 1;25(19):4320-4. doi: 10.1016/j.bmcl.2015.07.065.
Ramaiah Muthyala 1,  Woo Shik Shin 2,  Jiashu Xie 3,  Yuk Yin Sham 4
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 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.
  • 3 Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, United States.
  • 4 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: [email protected].
PMID: 26264503 DOI: 10.1016/j.bmcl.2015.07.065
Abstract

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.

Keywords

Drug resistance; HDAC; Leukemia; Pyrithione; Thiohydroxamic acid.

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