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Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

ABSTRACT: Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

PROVIDER: PRJNA740317 | ENA |

REPOSITORIES: ENA

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Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

Project description:Affymetrix SNP6.0 array data used to reveal predictive biomarkers of tumour sensitivity to MI-773 . MI-773 is a recently developed small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) proto-oncogene. Here we report an integrative pharmacogenomic study to gain further insights into the therapeutic potential of the compound

2021-10-27 | GSE178763 | GEO

Pharmacogenomic characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

Project description:MI-773 is a recently developed small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) proto-oncogene. Here we report an integrative pharmacogenomic study to gain further insights into the therapeutic potential of the compound.

2021-10-27 | GSE152529 | GEO

Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers.

Project description: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.

| S-EPMC8553758 | biostudies-literature

Pharmacogenomic characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

Project description:Pharmacogenomic characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

| PRJNA639587 | ENA

Expression data from neuroblastoma cells treated with MI-773

Project description:Neuroblastoma (NB) is a common pediatric malignancy tumor with poor outcome. Recent studies show that MDM2 protein inhibitors are promising anti-cancer agents. MI-773 is a novel and specific antagonist of MDM2 and the molecular mechanisms of MI-773 in neuroblastoma are still unclear. In this study, we used microarrays to analyze the global change in gene expression as a result of MI-773 treatment in the human neuroblastoma cell line SH-SY5Y.

2021-08-06 | GSE174450 | GEO

Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma.

Project description:Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common childhood extracranial malignant tumor. In NB, somatic mutations of the tumor suppressor, p53, are exceedingly rare. Unlike in adult tumors, the majority of p53 downstream functions are still intact in NB cells with wild-type p53. Thus, restoring p53 function by blocking its interaction with p53 suppressors such as MDM2 is a viable therapeutic strategy for NB treatment. Herein, we show that MDM2 inhibitor SAR405838 is a potent therapeutic drug for NB. SAR405838 caused significantly decreased cell viability of p53 wild-type NB cells and induced p53-mediated apoptosis, as well as augmenting the cytotoxic effects of doxorubicin (Dox). In an in vivo orthotopic NB mouse model, SAR405838 induced apoptosis in NB tumor cells. In summary, our data strongly suggest that MDM2-specific inhibitors like SAR405838 may serve not only as a stand-alone therapy, but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact MDM2-p53 axis.

| S-EPMC5347730 | biostudies-literature

Project description:Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

| PRJNA750602 | ENA

Expression data from neuroblastoma cells treated with MI-773

Project description:Expression data from neuroblastoma cells treated with MI-773

| PRJNA729997 | ENA

MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1.

Project description:Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G2/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.

| S-EPMC8548782 | biostudies-literature

Zea mays cultivar:RSQ-773

Project description:Zea mays RSQ-773 Transcriptome

| PRJNA493362 | ENA