Download MendeleyStereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.
Huber, K.V.M., Salah, E., Radic, B., Gridling, M., Elkins, J.M., Stukalov, A., Jemth, A., Gokturk, C., Sanjiv, K., Stromberg, K., Pham, T., Berglund, U.W., Colinge, J., Bennett, K.L., Loizou, J.I., Helleday, T., Knapp, S., Superti-Furga, G.(2014) Nature 508: 222
- PubMed: 24695225
- DOI: https://doi.org/10.1038/nature13194
- Primary Citation of Related Structures:
4C9W, 4C9X - PubMed Abstract:
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.
Organizational Affiliation:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
