4C9X

Crystal structure of NUDT1 (MTH1) with S-crizotinib

Summary for 4C9X

• Entry DOI: 10.2210/pdb4c9x/pdb
• Related: 4C9W
• Descriptor: 7,8-DIHYDRO-8-OXOGUANINE TRIPHOSPHATASE, 3-[(1S)-1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY]-5-(1-PIPERIDIN-4-YLPYRAZOL-4-YL)PYRIDIN-2-AMINE, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: hydrolase, crizotinib
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform p18: Cytoplasm. Isoform p26: Cytoplasm: P36639
• Total number of polymer chains: 1
• Total formula weight: 19065.69

Authors

Elkins, J.M.,Salah, E.,Huber, K.,Superti-Furga, G.,Abdul Azeez, K.R.,Krojer, T.,von Delft, F.,Bountra, C.,Edwards, A.,Knapp, S. (deposition date: 2013-10-03, release date: 2014-04-02, Last modification date: 2023-12-20)

Primary citation

Huber, K.V.M.,Salah, E.,Radic, B.,Gridling, M.,Elkins, J.M.,Stukalov, A.,Jemth, A.,Gokturk, C.,Sanjiv, K.,Stromberg, K.,Pham, T.,Berglund, U.W.,Colinge, J.,Bennett, K.L.,Loizou, J.I.,Helleday, T.,Knapp, S.,Superti-Furga, G.
Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.
Nature, 508:222-, 2014

PubMed 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.

PubMed: 24695225
DOI: 10.1038/NATURE13194

Experimental method

X-RAY DIFFRACTION (1.2 Å)