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Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target

Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target

Manuel Ellermann, Ashley Eheim, Fredrik Rahm, Jenny Viklund, Judith Guenther, Martin Andersson, Ulrika Ericsson, Rickard Forsblom, Tobias Ginman, Johan Lindström, Camilla Silvander, Lionel Trésaugues, Anja Giese, etc.

ACS Chem Biol. 2017 Aug 18;12(8):1986-1992.

PMID: 28679043

Abstract:

MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between these two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published. Despite superior cellular target engagement and pharmacokinetic properties, inhibition of MTH1 with BAY-707 resulted in a clear lack of in vitro or in vivo anticancer efficacy either in mono- or in combination therapies. Therefore, we conclude that MTH1 is dispensable for cancer cell survival.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP2109805969	BAY-707		2109805-96-9	Price

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