Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Huber, K., V., Salah, E., Radic, B., Gridling, M., Elkins, J., M., Stukalov, A., Jemth, A., S., Göktürk, C., Sanjiv, K., Strömberg, K., Pham, T., Berglund, U., W., Colinge, J., Bennett, K., L., Loizou, J., I., Helleday, T., Knapp, S., & Superti-Furga, G. Nature, 2014. abstract bibtex 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.
@article{
title = {Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy},
type = {article},
year = {2014},
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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.},
bibtype = {article},
author = {Huber, Kilian V.M. and Salah, Eidarus and Radic, Branka and Gridling, Manuela and Elkins, Jonathan M. and Stukalov, Alexey and Jemth, Ann Sofie and Göktürk, Camilla and Sanjiv, Kumar and Strömberg, Kia and Pham, Therese and Berglund, Ulrika Warpman and Colinge, Jacques and Bennett, Keiryn L. and Loizou, Joanna I. and Helleday, Thomas and Knapp, Stefan and Superti-Furga, Giulio},
journal = {Nature}
}
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