Novel class of potent and cellularly active inhibitors de-validates MTH1 as broad-spectrum cancer target.

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 anti-cancer efficacy either in mono- or in combination-therapies. Therefore we conclude that MTH1 is dispensable for cancer cell survival.