| http://purl.uniprot.org/citations/24695225 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/24695225 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/24695225 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.org/dc/terms/identifier | "doi:10.1038/nature13194"xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.org/dc/terms/identifier | "doi:10.1038/nature13194"xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Bennett K.L."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Bennett K.L."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Colinge J."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Colinge J."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Knapp S."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Knapp S."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Elkins J.M."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Elkins J.M."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Superti-Furga G."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Superti-Furga G."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Berglund U.W."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Berglund U.W."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Gokturk C."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Gokturk C."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Gridling M."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Gridling M."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Helleday T."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Helleday T."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Huber K.V."xsd:string |
| http://purl.uniprot.org/citations/24695225 | http://purl.uniprot.org/core/author | "Huber K.V."xsd:string |