Publication Date:
2014-04-04
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150021/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huber, Kilian V M -- Salah, Eidarus -- Radic, Branka -- Gridling, Manuela -- Elkins, Jonathan M -- Stukalov, Alexey -- Jemth, Ann-Sofie -- Gokturk, Camilla -- Sanjiv, Kumar -- Stromberg, Kia -- Pham, Therese -- Berglund, Ulrika Warpman -- Colinge, Jacques -- Bennett, Keiryn L -- Loizou, Joanna I -- Helleday, Thomas -- Knapp, Stefan -- Superti-Furga, Giulio -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- F 4711/Austrian Science Fund FWF/Austria -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Apr 10;508(7495):222-7. doi: 10.1038/nature13194. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. ; Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. ; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17121 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695225" target="_blank"〉PubMed〈/a〉
Keywords:
Aminoquinolines/pharmacology
;
Animals
;
Antineoplastic Agents/chemistry/*pharmacology
;
Colonic Neoplasms/drug therapy/genetics/pathology
;
Crystallization
;
DNA Breaks, Single-Stranded/drug effects
;
DNA Repair
;
DNA Repair Enzymes/*antagonists & inhibitors/biosynthesis/chemistry/*metabolism
;
Disease Models, Animal
;
Female
;
Homeostasis/drug effects
;
Humans
;
Mice
;
Mice, SCID
;
Models, Molecular
;
Nucleotides/metabolism
;
Phosphoric Monoester Hydrolases/*antagonists &
;
inhibitors/biosynthesis/chemistry/*metabolism
;
Protein Conformation
;
Protein Kinase Inhibitors/chemistry/*pharmacology
;
Proteomics
;
Proto-Oncogene Proteins/genetics
;
Pyrazoles/chemistry/*pharmacology
;
Pyridines/chemistry/*pharmacology
;
Substrate Specificity
;
Xenograft Model Antitumor Assays
;
ras Proteins/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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