期刊
NATURE
卷 508, 期 7495, 页码 215-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13181
关键词
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资金
- Torsten and Ragnar Soderberg Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Research Council
- European Research Council
- Swedish Cancer Society
- Swedish Children's Cancer Foundation
- AFA insurance
- Swedish Pain Relief Foundation
- Cancer Society in Stockholm
- Wenner-Gren Foundations
- Swedish Foundation for Strategic Research
- Dutch Cancer Society
- EMBO LTF
- Region Vastra Gotaland
- BioCARE
- Swiss National Science Foundation
- Nicholson Exchange Program
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.
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