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Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

DOI: 10.1021/acs.jmedchem.5b01760 DOI Help
PMID: 26878898 PMID Help

Authors: Jason G. Kettle (AstraZeneca) , Husam Alwan (AstraZeneca) , Michal Bista (AstraZeneca) , Jason Breed (AstraZeneca) , Nichola L. Davies (AstraZeneca) , Kay Eckersley (AstraZeneca) , Shaun Fillery (AstraZeneca) , Kevin M. Foote (AstraZeneca) , Louise Goodwin (AstraZeneca) , David R. Jones (AstraZeneca) , Helena Käck (AstraZeneca) , Alan Lau (AstraZeneca) , J. Willem M. Nissink (AstraZeneca) , Jon Read (AstraZeneca) , James S. Scott (AstraZeneca) , Ben Taylor (AstraZeneca) , Graeme Walker (AstraZeneca) , Lisa Wissler (AstraZeneca) , Marta Wylot (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: February 2016

Open Access Open Access

Abstract: Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the “housekeeping” enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.

Subject Areas: Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 02/03/2016 11:44

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