Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors
Targeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is s...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2018
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| _version_ | 1797060623451815936 |
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| author | Stefaniak, J Lewis, A Conole, D Galan, S Bataille, C Wynne, G Castaldi, M Lundbäck, T Russell, A Huber, K |
| author_facet | Stefaniak, J Lewis, A Conole, D Galan, S Bataille, C Wynne, G Castaldi, M Lundbäck, T Russell, A Huber, K |
| author_sort | Stefaniak, J |
| collection | OXFORD |
| description | Targeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is still limited. The arylmethylidenepyrazolinone SJ-172550 has been reported as a selective MDMX antagonist; yet, uncertainties about its mechanism of action have raised doubts about its use as a chemical probe. Here, we show that, in addition to its unclear mode of action, SJ-172550 is unstable in aqueous buffers, giving rise to side products of unknown biological activity. Using an SJ-172550-derived affinity probe, we observed promiscuous binding to cellular proteins whereas cellular thermal shift assays did not reveal a stabilizing effect on MDMX. Overall, our results raise further questions about the interpretation of data using SJ-172550 and related compounds to investigate cellular phenotypes. |
| first_indexed | 2024-03-06T20:19:42Z |
| format | Journal article |
| id | oxford-uuid:2d5ebe74-37ab-4948-86e7-2e8c28ff5244 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:19:42Z |
| publishDate | 2018 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:2d5ebe74-37ab-4948-86e7-2e8c28ff52442022-03-26T12:42:35ZChemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2d5ebe74-37ab-4948-86e7-2e8c28ff5244EnglishSymplectic Elements at OxfordAmerican Chemical Society2018Stefaniak, JLewis, AConole, DGalan, SBataille, CWynne, GCastaldi, MLundbäck, TRussell, AHuber, KTargeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is still limited. The arylmethylidenepyrazolinone SJ-172550 has been reported as a selective MDMX antagonist; yet, uncertainties about its mechanism of action have raised doubts about its use as a chemical probe. Here, we show that, in addition to its unclear mode of action, SJ-172550 is unstable in aqueous buffers, giving rise to side products of unknown biological activity. Using an SJ-172550-derived affinity probe, we observed promiscuous binding to cellular proteins whereas cellular thermal shift assays did not reveal a stabilizing effect on MDMX. Overall, our results raise further questions about the interpretation of data using SJ-172550 and related compounds to investigate cellular phenotypes. |
| spellingShingle | Stefaniak, J Lewis, A Conole, D Galan, S Bataille, C Wynne, G Castaldi, M Lundbäck, T Russell, A Huber, K Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors |
| title | Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors |
| title_full | Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors |
| title_fullStr | Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors |
| title_full_unstemmed | Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors |
| title_short | Chemical instability and promiscuity of arylmethylidenepyrazolinone-based MDMX inhibitors |
| title_sort | chemical instability and promiscuity of arylmethylidenepyrazolinone based mdmx inhibitors |
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