Identification of potent and selective MTH1 inhibitors. Issue 6 (15th March 2016)

• Record Type: Journal Article
• Authors: Petrocchi, Alessia; Leo, Elisabetta; Reyna, Naphtali J.; Hamilton, Matthew M.; Shi, Xi; Parker, Connor A.; Mseeh, Faika; Bardenhagen, Jennifer P.; Leonard, Paul; Cross, Jason B.; Huang, Sha; Jiang, Yongying; Cardozo, Mario; Draetta, Giulio; Marszalek, Joseph R.; Toniatti, Carlo; Jones, Philip; Lewis, Richard T.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 6(2016)
• Page Start: 1503
• Page End: 1507
• Publication Date: 2016-03-15
• Subjects: MTH1 inhibitors -- Antitumor -- IACS-4759 -- 2-Aminopyrimidine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.02.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification ofIACS-4759 (compound5 ), 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.