MI-773 / Ascenta, Sanofi - LARVOL DELTA

Differentially Expressed Genes and Biological Pathways in Moyamoya Disease: A Systematic Review and Meta-analysis of Transcriptomic Studies. (PubMed, Transl Stroke Res) - "Gene-drug interaction analysis highlighted MI-773 and MLN 8237 as potential MMD therapy. This study identifies distinct biological pathways that are dysregulated in key tissues of MMD patients. Given the current limited treatment options for MMD, our findings offer potential biomarkers for risk stratification and novel therapeutic targets that could pave the way for improved management of this debilitating disease."

Journal • Retrospective data • Review • Cardiovascular • CNS Disorders • Vascular Neurology • BDNF

Anti-cancer activity elucidation of geissolosimine as an MDM2-p53 interaction inhibitor: An in-silico study. (PubMed, PLoS One) - "The predicted pIC50 value of Geissolosimine, was 7.013 M. Moreover, Geissolosimine showed 0.62% structural similarity to 'SAR405838' (i.e., a clinical trial inhibitor for MDM2-p53 interaction inhibition); and a docking score of -10.9 kcal/mol that was higher than the 'SAR405838'.100 ns molecular dynamics simulation (MDS) was performed to validate the docking result and it exhibited better binding stability to MDM2. The pharmacokinetic & drug-likeness analysis suggested that Geissolosimine had potential to be a drug-like compound. However, in vitro & in vivo assays will be required to validate this study."

Journal • Oncology

Twist1 forms a trimeric complex with p53 and MDM2 and attenuates the efficacy of MDM2 inhibitors (EACR 2024) - "The interaction is direct, as demonstrated by GST pull downs, and occurs under para-physiological conditions, as shown by TurboID proximity-dependent biotinylation experiments.Modulation of Twist1 expression in p53 wild type/MDM2 overexpressing sarcoma cell models affects p53 and the response to MDM2i (Nutlin-3a, Milademetan/DS-3032, Idasanutlin/RG7388, SAR405838). Conversely, ectopic Twist1 expression attenuates MDM2i efficacy. This effect depends on Twist1 binding to p53 and MDM2, as a Twist1 mutant defective for this binding loses the inhibitory capacity.Conclusion Twist forms a p53:Twist:MDM2 trimeric complex and, by enhancing MDM2-mediated degradation of p53, attenuates the efficacy of MDM2i"

Clinical • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • MDM2 • TWIST1

Comparison of three-dimensional cell culture techniques of dedifferentiated liposarcoma and their integration with future research. (PubMed, Front Cell Dev Biol) - "All samples were processed for histopathological analysis (HE, IHC and DNAscope™), Western blot, and qPCR; moreover, 3D collagen-based models were treated with different doses of SAR405838, a well-known inhibitor of MDM2, and cell viability was assessed in comparison to 2D model drug response...3D collagen samples showed higher cell viability after SAR40538 treatment than 2D models, while cells sensitive to the drug died by apoptosis or necrosis. Our results prompt us to extend our investigation by applying our 3D models to further oncological relevant applications, which may help address unresolved questions about dedifferentiated liposarcoma biology."

Journal • Preclinical • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

Three dimensional models of dedifferentiated liposarcoma cell lines: scaffold-based and scaffold-free approaches. (PubMed, Hum Cell) - "After treatment with MDM2 inhibitor SAR405838, DDLPS spheroids demonstrated different sensitivity patterns from 2D models. Taken together, we believed that 3D models would have a possibility to provide us a new predictability of efficacy and toxicity, and considered as one important process in in vitro pre-clinical phase prior to moving forward to clinical trials."

Journal • Preclinical • Liposarcoma • Oncology • Sarcoma • Solid Tumor • MDM2

Deep Multi-Omics Profiling in Cytogenetically Poor-Risk AML (ASH 2022) - "For example, we validated TP53 WT status as a determinant of response to MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) and we found that within the TP53-WT group of patients, good-responders have a significantly lower expression of TP53 pathway genes at diagnosis compared to non-responders. Altogether, these findings demonstrate the feasibility of simultaneously generating multi-omics data from several different platforms in AML primary samples and highlights that integrative analysis will increase our understanding of the biology of the disease and its therapeutic vulnerabilities."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • DEK • ETV6 • GATA2 • GNAS • KMT2A • NUP214 • PBX3

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma. (PubMed, Front Oncol) - "Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS."

Journal • Review • Gene Therapies • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation • MDM2 • TMB

Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy. (PubMed, Int J Mol Sci) - "With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study...Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor 3 to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy."

IO biomarker • Journal • Oncology • IDO1

Correction: SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma. (PubMed, Clin Cancer Res) - No abstract available

Journal • Liposarcoma • Oncology • Sarcoma • Solid Tumor

Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers. (PubMed, NPJ Precis Oncol) - "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 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."

Biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Lymphoma • Melanoma • Oncology • Sarcoma • Solid Tumor • MDM2

MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1. (PubMed, Oncol Lett) - "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."

Journal • Neuroblastoma • Neuroendocrine Tumor • Oncology • Pediatrics • Solid Tumor • MDM2

Advances in targeted therapy for osteosarcoma based on molecular classification. (PubMed, Pharmacol Res) - "Therefore, we indicated the importance of molecular classification on the targeted therapy for osteosarcoma. And the stratification of patients based on the genetic characteristics of osteosarcoma will help to obtain a better therapeutic response to targeted therapies, bringing us closer to the era of personalized medicine."

Journal • Review • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Inverse and reciprocal regulation of p53/p21 and Bmi-1 modulates vasculogenic differentiation of dental pulp stem cells. (PubMed, Cell Death Dis) - "Conversely, induction of p53 expression with small molecule inhibitors of the p53-MDM2 binding (MI-773, APG-115) was sufficient to inhibit VEGF-induced vasculogenic differentiation. Further, direct inhibition of Bmi-1 with PTC-209 resulted in blockade of capillary-like sprout formation. Collectively, these data demonstrate that p53/p21 functions through Bmi-1 to prevent the vasculogenic differentiation of DPSC."

Journal • Targeted Protein Degradation • Transplantation • BMI1 • CD31 • CDH5 • CDKN1A • KDR • MDM2

Modulation of MDM2 alters the metabolomic programming of dedifferentiated liposarcoma and its sensitivity to cholesterol inhibition (AACR 2018) - "Modulation of MDM2 alters cholesterol metabolism in DDLPS and may serve as druggable target."

Sarcoma

Targeted MDM2 degradation as a novel and efficacious cancer therapy (AACR 2018) - "Currently, numerous drugs inhibiting the MDM2-p53 interaction, such as RG7112 (Hoffmann-La Roche), MI-773 (Sanofi) and DS-3032b (Daiichi Sankyo), have entered different stages of clinical trials. More importantly, the MDM2 degraders showed great efficacy in inducing complete tumor regression or strong tumor growth inhibition in human leukemia xenograft models and significantly improved survival in disseminated human leukemia models in mice at well-tolerated dose-schedules. Our data provide strong preclinical rationale to further develop MDM2 degraders as a new class of therapy for the treatment of human acute leukemia and potentially other types of human cancer."

Leukemia

[VIRTUAL] Integration of Deep Multi-Omics Profiling Veals New Insights into the Biology of Poor-Risk Acute Myeloid Leukemia (ASH 2020) - "Collectively, t(6;9) primary samples also showed a selective drug sensitivity to XPO1 (selinexor and eltanexor) and JAK inhibitors (ruxolitinib, tofacitinib and momelotinib) compared to other cytogenetic risk groups. On the other hand, a comparison of in vitro drug sensitivity data with genomic data of our entire cohort of patients demonstrated that TP53 wt AMLs (n=37) were more sensitive to all four MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) compared to TP53 mutated cases (n=13). Comparisons of transcriptomics with the in vitro sensitivity to drugs included in early/late phase AML clinical trials, identified signatures of response associated with MDM2 and Aurora B kinase (AZD1152-HQPA) inhibitors...Functionally, group A presented with elevated HOXA10 protein expression and enhanced in vitro response to genotoxic drugs and cell cycle inhibitors when compared to group B leukemia. Conclusions : Our study demonstrates the feasibility of simultaneously..."

IO Biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • FOXO3 • GATA2 • KIT • MLL • NUP214 • TP53

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. (PubMed, Acta Pharm Sin B) - "Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions."

Journal • Review • Oncology • Targeted Protein Degradation

Combined inhibition of MDM2 and MEK for KRAS mutant non-small cell lung cancer (AACR 2014) - Presentation time: Sunday, Apr 06, 2014, 1:00 PM - 5:00 PM; Abstract #741; “In KRAS mutant NSCLC cell lines with wild-type p53, pimasertib (MEKi) and SAR405838 (MDM-2i) led to upregulation of BIM and PUMA respectively. Induction of apoptosis and cell cycle arrest correlated with in vitro efficacy, and the combination exhibited marked in vivo activity against KRAS mutant p53 wild-type NSCLC xenograft tumors."

Preclinical • Non Small Cell Lung Cancer • Oncology

Disruption of the MDM2-p53 interaction synergizes with MEK inhibition to induce cell death and promote tumor regression in p53 wild-type, Ras or Raf-mutant tumor models (AACR 2014) - Presentation time: Sunday, Apr 06, 2014, 1:00 PM - 5:00 PM; Abstract #805; “...combination of SAR405838 with the MEK inhibitor pimasertib resulted in p53 pathway activation, inhibition of pERK levels, induction of the apoptotic mediators PUMA and BIM, induction of phosphatidyl serine exposure, and induction of caspase activity....In cell line and patient-derived xenografts in vivo, the combination of SAR405838 and pimasertib resulted in greater anti-tumor activity than single agents and induced regression in K-ras, N-ras and B-raf mutant tumor models derived from different tissue types, including complete regressions in multiple models."

Preclinical • Oncology

Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells. (PubMed) - Oncotarget - "...The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial...In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients."

Journal • Biosimilar • Oncology • Thyroid Cancer

Ablation of cancer stem cells by therapeutic inhibition of the MDM2-p53 interaction in mucoepidermoid carcinoma. (PubMed, Clin Cancer Res) - "Collectively, these data demonstrate that MI-773 reduces the fraction of cancer stem cells, suggesting that patients with mucoepidermoid carcinoma might benefit from therapeutic inhibition of the MDM2-p53 interaction."

Cancer stem cells • Journal

A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance. (PubMed, Mater Sci Eng C Mater Biol Appl) - "For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors."

Combination therapy • Journal

BCR-ABL1 p190 in CML: A Minor Breakpoint with a Major Impact (ASH 2019) - " CML patients with p190 had a median age of 72.5 years at the diagnosis (range: 50-80) and all received imatinib as a frontline treatment. Only one patient achieved a fluctuating major molecular response (MMR) by 12 months while the rest of the patients showed primary resistance to treatment and were shifted to a 2nd line TKI, nilotinib (n=2) or proceeded to HSCT (n=1)...DSRT results also revealed increased sensitivity of primary Ph+ ALL-p190 cells to Src-inhibitors (dasatinib and saracatinib), glucocorticoids and MDM2 inhibitors/TP53 activators (SAR405838 and idasanutlin)... In CML, p190 isoform of BCR-ABL1 is associated with distinct features and should be considered as a high-risk group. Combining clinical, genomic, phosphorylation and drug sensitivity data, we demonstrated that p190 activates specific cancer pathways, notably Src signaling and interferon pathways. Data also suggests that CML patients with p190 could benefit from broad spectrum TKI with Src inhibiting..."

IO Biomarker • ABL1 • DNMT3A • TP53

A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. (PubMed, Br J Cancer) - P1; "The safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed."

Biomarker • Clinical • Journal • P1 data

Broad spectrum activity of the MDM2 inhibitor MI-773 in hematologic and solid cancer cell lines in-vitro and determination of predictive biomarkers (AACR-NCI-EORTC 2019) - "The Compare analysis of MI-773 with 44 targeted agents and 250 cytotoxic agents in 40 to 117 tumor cell lines showed the highest similarity with p53/MDM2 inhibitors Nutlin-3a and YH239-EE with Spearman correlation coefficients of 0,71 and 0,56, a clear indication that biological testing’s in cell line panels allows identification of the mechanism of action of novel compounds. The present study demonstrated that the MDM2 inhibitor MI-773 could be used in a broad range of hematological and solid tumor types, however, with the determination of TP53 as a prerequisite. MDM2 inhibitors should be evaluated in p53 wild type melanomas, mesotheliomas, kidney, stomach, and breast cancers as well as in ALL, AML, and multiple myelomas."