| Added by | mollevi |
|---|---|
| Last modified by | jacques.colinge |
| Group name | EquipeJC |
| Item Type | Journal Article |
| Title | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy |
| Creator | Huber et al. |
| Author | K. V. Huber |
| Author | E. Salah |
| Author | B. Radic |
| Author | M. Gridling |
| Author | J. M. Elkins |
| Author | A. Stukalov |
| Author | A. S. Jemth |
| Author | C. Gokturk |
| Author | K. Sanjiv |
| Author | K. Stromberg |
| Author | T. Pham |
| Author | U. W. Berglund |
| Author | J. Colinge |
| Author | K. L. Bennett |
| Author | J. I. Loizou |
| Author | T. Helleday |
| Author | S. Knapp |
| Author | G. 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. |
| Publication | Nature |
| Volume | 508 |
| Pages | 222-7 |
| Date | Apr 10 2014 |
| Journal Abbr | Nature |
| DOI | 10.1038/nature13194 |
| ISSN | 1476-4687 (Electronic) 0028-0836 (Linking) |
| Tags | Aminoquinolines/pharmacology, Animals, Antineoplastic Agents/chemistry/*pharmacology, Colonic Neoplasms/drug therapy/genetics/pathology, Crystallization, Disease Models, Animal, DNA Breaks, Single-Stranded/drug effects, DNA Repair, DNA Repair Enzymes/*antagonists & inhibitors/biosynthesis/chemistry/*metabolism, Female, Homeostasis/drug effects, Humans, inhibitors/biosynthesis/chemistry/*metabolism, Mice, Mice, SCID, Models, Molecular, Nucleotides/metabolism, original, Phosphoric Monoester Hydrolases/*antagonists &, postdoc, Protein Conformation, Protein Kinase Inhibitors/chemistry/*pharmacology, Proto-Oncogene Proteins/genetics, Pyrazoles/chemistry/*pharmacology, Pyridines/chemistry/*pharmacology, ras Proteins/genetics, Substrate Specificity, Xenograft Model Antitumor Assays |
| Date Added | 2018/11/14 - 11:48:35 |
| Date Modified | 2019/10/22 - 21:21:02 |
| Notes and Attachments | (Note) (Note) 24695225 (Attachment) |
Institut de Recherche en Cancérologie de
