The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy
Open accessAbstract
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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Metadata
- Authors
- Huber, K. V. M., Salah, E., Radic, B., Gridling, M., Elkins, J. M., Stukalov, A., Jemth, A.-S., Göktürk, C., Sanjiv, K., Strömberg, K., Pham, T., Berglund, U. W., Colinge, J., Bennett, K. L., Loizou, J. I., Helleday, T., Knapp, S., & Superti-Furga, G.
- Venue
- Nature
- Published
- 2014-04-02
- Volume
- 508
- Issue
- 7495
- Pages
- 222-227
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1981258651
- Cited by
- 395
- References
- 29
- FWCI
- 20.44
- Type
- journal article
- Language
- en
- Open access
- green
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- Huber, K. V. M., Salah, E., Radic, B., Gridling, M., Elkins, J. M., Stukalov, A., Jemth, A.-S., Göktürk, C., Sanjiv, K., Strömberg, K., Pham, T., Berglund, U. W., Colinge, J., Bennett, K. L., Loizou, J. I., Helleday, T., Knapp, S., & Superti-Furga, G. (2014). Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature. https://doi.org/10.1038/nature13194
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