Identification of potent and selective MTH1 inhibitors

Alessia Petrocchi, Elisabetta Leo, Naphtali J. Reyna, Matthew M. Hamilton, Xi Shi, Connor A. Parker, Faika Mseeh, Jennifer P. Bardenhagen, Paul Leonard, Jason B. Cross, Sha Huang, Yongying Jiang, Mario Cardozo, Giulio Draetta, Joseph R. Marszalek, Carlo Toniatti, Philip Jones, Richard T. Lewis

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic stability in microsomes. This compound robustly inhibited MTH1 activity in cells and proved to be an excellent tool for interrogation of the utility of MTH1 inhibition in the context of oncology.

Original languageEnglish (US)
Pages (from-to)1503-1507
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number6
DOIs
StatePublished - 2016

Keywords

  • 2-Aminopyrimidine
  • Antitumor
  • IACS-4759
  • MTH1 inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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