Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy

Kilian V. M. Huber, Eidarus Salah, Branka Radic, Manuela Gridling, Jonathan M. Elkins, Alexey Stukalov, Ann-Sofie Jemth, Camilla Göktürk, Kumar Sanjiv, Kia Strömberg, Therese Pham, Ulrika Warpman Berglund, Jacques Colinge, Keiryn L. Bennett, Joanna I. Loizou, Thomas Helleday, Stefan Knapp and Giulio Superti-Furga ()
Additional contact information
Kilian V. M. Huber: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
Eidarus Salah: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Branka Radic: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
Manuela Gridling: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
Jonathan M. Elkins: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Alexey Stukalov: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
Ann-Sofie Jemth: Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden
Camilla Göktürk: Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden
Kumar Sanjiv: Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden
Kia Strömberg: Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden
Therese Pham: Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden
Ulrika Warpman Berglund: Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden
Jacques Colinge: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
Keiryn L. Bennett: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
Joanna I. Loizou: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
Thomas Helleday: Science for Life Laboratory, Karolinska Institutet, 17121 Stockholm, Sweden
Stefan Knapp: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria

Nature, 2014, vol. 508, issue 7495, 222-227

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13194

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