3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition

Vishal Patil, Quaovi H. Sodji, James R. Kornacki, Milan Mrksich*, Adegboyega K. Oyelere

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines.

Original languageEnglish (US)
Pages (from-to)3492-3506
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 9 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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