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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.

Original publication

DOI

10.1038/nature13194

Type

Journal article

Journal

Nature

Publication Date

10/04/2014

Volume

508

Pages

222 - 227

Keywords

Aminoquinolines, Animals, Antineoplastic Agents, Colonic Neoplasms, Crystallization, DNA Breaks, Single-Stranded, DNA Repair, DNA Repair Enzymes, Disease Models, Animal, Female, Homeostasis, Humans, Mice, Mice, SCID, Models, Molecular, Nucleotides, Phosphoric Monoester Hydrolases, Protein Conformation, Protein Kinase Inhibitors, Proteomics, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Pyrazoles, Pyridines, Substrate Specificity, Xenograft Model Antitumor Assays, ras Proteins