Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors

Taha Y. Taha, Shaimaa M. Aboukhatwa, Rachel C. Knopp, Naohiko Ikegaki, Hazem Abdelkarim, Jayaprakash Neerasa, Yunlong Lu, Raghupathi Neelarapu, Thomas W. Hanigan, Gregory R.J. Thatcher, Pavel A. Petukhov

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 μM. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.

Original languageEnglish (US)
Pages (from-to)824-829
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number8
DOIs
StatePublished - Aug 10 2017
Externally publishedYes

Keywords

  • HDAC8
  • Histone deacetylase
  • hydroxamate
  • inhibitor
  • tetrahydroisoquinoline

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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