MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

作者：Gad Helge; Koolmeister Tobias; Jemth Ann Sofie; Eshtad Saeed; Jacques Sylvain A; Strom Cecilia E; Svensson Linda M; Schultz Niklas; Lundback Thomas; Einarsdottir Berglind Osk; Saleh Aljona; Gokturk Camilla; Baranczewski Pawel; Svensson Richard; Berntsson Ronnie P A; Gustafsson Robert; Stromberg Kia; Sanjiv Kumar; Jacques Cordonnier Marie Caroline; Desroses Matthieu; Gustavsson Anna Lena; Olofsson Roger; Johansson Fredrik; Homan Evert J; Loseva Olga

来源：Nature, 2014, 508(7495): 215-+.

DOI：10.1038/nature13181

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

• 出版日期2014-4-10