Thiol-based potent and selective HDAC6 inhibitors promote tubulin acetylation and T-regulatory cell suppressive function

Mariana C.F. Segretti, Gian Paolo Vallerini, Camille Brochier, Brett Langley, Liqing Wang, Wayne W. Hancock, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.

Original languageEnglish (US)
Pages (from-to)1156-1161
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume6
Issue number11
DOIs
StatePublished - Nov 12 2015

Keywords

  • 1,2,3,4-tetrahydroquinoline
  • 8-aminoquinoline
  • HDAC6-selective inhibitors
  • Treg
  • mercaptoacetamides

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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