Identification of potent and selective MTH1 inhibitors

Bioorg Med Chem Lett. 2016 Mar 15;26(6):1503-1507. doi: 10.1016/j.bmcl.2016.02.026. Epub 2016 Feb 11.

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.

Keywords: 2-Aminopyrimidine; Antitumor; IACS-4759; MTH1 inhibitors.

MeSH terms

  • DNA Repair Enzymes / antagonists & inhibitors*
  • DNA Repair Enzymes / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Phosphoric Monoester Hydrolases
  • 8-oxodGTPase
  • DNA Repair Enzymes