Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-04-02

AUTHORS

Kilian V. M. Huber, Eidarus Salah, Branka Radic, Manuela Gridling, Jonathan M. Elkins, Alexey Stukalov, Ann-Sofie Jemth, Camilla Göktürk, Kumar Sanjiv, Kia Strömberg, Therese Pham, Ulrika Warpman Berglund, Jacques Colinge, Keiryn L. Bennett, Joanna I. Loizou, Thomas Helleday, Stefan Knapp, Giulio Superti-Furga

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. More... »

PAGES

222

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature13194

DOI

http://dx.doi.org/10.1038/nature13194

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1020098338

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24695225


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