Journal
NATURE
Volume 508, Issue 7495, Pages 222-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13194
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Funding
- Austrian Academy of Sciences
- GEN-AU initiative of the Austrian Federal Ministry for Science and Research
- European Union
- SGC, a registered charity [1097737]
- Canadian Institutes for Health Research
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Pfizer
- Eli Lilly
- Takeda
- AbbVie
- Novartis Research Foundation
- Boehringer Ingelheim
- Ontario Ministry of Research and Innovation
- Wellcome Trust [092809/Z/10/Z]
- European Union [278568]
- Torsten and Ragnar Soderberg Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Research Council
- European Research Council
- Swedish Cancer Society
- European Union FP7 Career Integration Grant [PCIG11-GA-2012-321602]
- FWF Grant [P24766-B20]
- Austrian Science Fund (FWF) [P24766] Funding Source: Austrian Science Fund (FWF)
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Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.
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