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

Ramaiah Muthyala; Woo Shik Shin; Jiashu Xie; Yuk Yin Sham

doi:10.1016/j.bmcl.2015.07.065

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. Epub 2015 Jul 26.

Authors

Ramaiah Muthyala¹, Woo Shik Shin², Jiashu Xie³, Yuk Yin Sham⁴

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: muthy003@umn.edu.
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: shamx002@umn.edu.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Mice
Molecular Docking Simulation
Molecular Structure
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
Thiones / chemical synthesis
Thiones / chemistry
Thiones / pharmacology*

Substances

Histone Deacetylase Inhibitors
Pyridines
Thiones
pyrithione
Histone Deacetylases