Identification of potent and selective MTH1 inhibitors

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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.

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Acknowledgments

We thank Barbara Czako, Maria Emilia Di Francesco, Michael Soth and Wylie Palmer for helpful discussion.

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Present address: Cancer Research Technology-Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.

Present address: Nurix, 1700 Owens St Suite 290, San Francisco, CA 94158, USA.

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