Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2014
|
| _version_ | 1826264247446798336 |
|---|---|
| author | Huber, K Salah, E Radic, B Gridling, M Elkins, J Stukalov, A Jemth, A Göktürk, C Sanjiv, K Strömberg, K Pham, T Berglund, U Colinge, J Bennett, K Loizou, J Helleday, T Knapp, S Superti-Furga, G |
| author_facet | Huber, K Salah, E Radic, B Gridling, M Elkins, J Stukalov, A Jemth, A Göktürk, C Sanjiv, K Strömberg, K Pham, T Berglund, U Colinge, J Bennett, K Loizou, J Helleday, T Knapp, S Superti-Furga, G |
| author_sort | Huber, K |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-06T20:04:42Z |
| format | Journal article |
| id | oxford-uuid:28882238-b520-469b-8eb9-adce7a4ef327 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:04:42Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:28882238-b520-469b-8eb9-adce7a4ef3272022-03-26T12:13:25ZStereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:28882238-b520-469b-8eb9-adce7a4ef327EnglishSymplectic Elements at Oxford2014Huber, KSalah, ERadic, BGridling, MElkins, JStukalov, AJemth, AGöktürk, CSanjiv, KStrömberg, KPham, TBerglund, UColinge, JBennett, KLoizou, JHelleday, TKnapp, SSuperti-Furga, GActivated 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. |
| spellingShingle | Huber, K Salah, E Radic, B Gridling, M Elkins, J Stukalov, A Jemth, A Göktürk, C Sanjiv, K Strömberg, K Pham, T Berglund, U Colinge, J Bennett, K Loizou, J Helleday, T Knapp, S Superti-Furga, G Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. |
| title | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. |
| title_full | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. |
| title_fullStr | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. |
| title_full_unstemmed | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. |
| title_short | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. |
| title_sort | stereospecific targeting of mth1 by s crizotinib as an anticancer strategy |
| work_keys_str_mv | AT huberk stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT salahe stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT radicb stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT gridlingm stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT elkinsj stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT stukalova stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT jemtha stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT gokturkc stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT sanjivk stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT strombergk stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT phamt stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT berglundu stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT colingej stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT bennettk stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT loizouj stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT helledayt stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT knapps stereospecifictargetingofmth1byscrizotinibasananticancerstrategy AT supertifurgag stereospecifictargetingofmth1byscrizotinibasananticancerstrategy |