Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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, Crizotinib, 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