Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers
Abstract MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here,...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-10-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-021-00235-7 |
| _version_ | 1797428635738570752 |
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| author | Vincent Vuaroqueaux Hans R. Hendriks Hoor Al-Hasani Anne-Lise Peille Samayita Das Heinz-Herbert Fiebig |
| author_facet | Vincent Vuaroqueaux Hans R. Hendriks Hoor Al-Hasani Anne-Lise Peille Samayita Das Heinz-Herbert Fiebig |
| author_sort | Vincent Vuaroqueaux |
| collection | DOAJ |
| description | Abstract MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here, we explored the compound’s therapeutic potential in vitro using a panel of 274 annotated CLs derived from a diversity of tumours. MI-773 exhibited a pronounced selectivity and moderate potency, with anti-tumour activity in the sub-micromolar range in about 15% of the CLs. The most sensitive tumour types were melanoma, sarcoma, renal and gastric cancers, leukaemia, and lymphoma. A COMPARE analysis showed that the profile of MI-773 was similar to that of Nutlin-3a, the first potent inhibitor of p53–MDM2 interactions, and, in addition, had a superior potency. In contrast, it poorly correlates with profiles of compounds targeting the p53 pathway with another mechanism of action. OMICS analyses confirmed that MI-773 was primarily active in CLs with wild type TP53. In silico biomarker investigations revealed that the TP53 mutation status plus the aggregated expression levels of 11 genes involved in the p53 signalling pathway predicted sensitivity or resistance of CLs to inhibitors of p53–MDM2 interactions reliably. The results obtained for MI-773 could help to refine the selection of cancer patients for therapy. |
| first_indexed | 2024-03-09T09:01:44Z |
| format | Article |
| id | doaj.art-fa935edd769044dbbcb37ff0f6b1cc5a |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T09:01:44Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-fa935edd769044dbbcb37ff0f6b1cc5a2023-12-02T11:31:37ZengNature Portfolionpj Precision Oncology2397-768X2021-10-015111110.1038/s41698-021-00235-7Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkersVincent Vuaroqueaux0Hans R. Hendriks1Hoor Al-Hasani2Anne-Lise Peille3Samayita Das4Heinz-Herbert Fiebig54HF Biotec GmbHHendriks Pharmaceutical Consulting4HF Biotec GmbH4HF Biotec GmbH4HF Biotec GmbH4HF Biotec GmbHAbstract MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here, we explored the compound’s therapeutic potential in vitro using a panel of 274 annotated CLs derived from a diversity of tumours. MI-773 exhibited a pronounced selectivity and moderate potency, with anti-tumour activity in the sub-micromolar range in about 15% of the CLs. The most sensitive tumour types were melanoma, sarcoma, renal and gastric cancers, leukaemia, and lymphoma. A COMPARE analysis showed that the profile of MI-773 was similar to that of Nutlin-3a, the first potent inhibitor of p53–MDM2 interactions, and, in addition, had a superior potency. In contrast, it poorly correlates with profiles of compounds targeting the p53 pathway with another mechanism of action. OMICS analyses confirmed that MI-773 was primarily active in CLs with wild type TP53. In silico biomarker investigations revealed that the TP53 mutation status plus the aggregated expression levels of 11 genes involved in the p53 signalling pathway predicted sensitivity or resistance of CLs to inhibitors of p53–MDM2 interactions reliably. The results obtained for MI-773 could help to refine the selection of cancer patients for therapy.https://doi.org/10.1038/s41698-021-00235-7 |
| spellingShingle | Vincent Vuaroqueaux Hans R. Hendriks Hoor Al-Hasani Anne-Lise Peille Samayita Das Heinz-Herbert Fiebig Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers npj Precision Oncology |
| title | Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers |
| title_full | Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers |
| title_fullStr | Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers |
| title_full_unstemmed | Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers |
| title_short | Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers |
| title_sort | pharmacogenomics characterization of the mdm2 inhibitor mi 773 reveals candidate tumours and predictive biomarkers |
| url | https://doi.org/10.1038/s41698-021-00235-7 |
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