idasanutlin (RG7388) / Roche - LARVOL DELTA

Venetoclax and idasanutlin in relapsed/refractory AML: a non-randomized, open-label phase 1b trial. (PubMed, Blood) - P1 | "IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were pre-existing. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations."

IO biomarker • Journal • P1 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • BCL2 • IDH1 • IDH2 • RUNX1 • TP53

Idasanutlin Plus Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia: Results of the MIRROS Trial. (PubMed, Blood Adv) - P3 | "Adults (N=447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 intravenously on days 1 to 5 of 28-day cycles. Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML."

Journal • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • MDM2 • TP53

N2M2/NOA-20: Phase I/IIa umbrella trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation. (ASCO 2024) - P1/2 | "Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ)...The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug... N 2 M 2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients."

Clinical • P1/2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CDK4 • CDKN2A • CDKN2B

Interaction of Erastin, a ferroptosis-inducing agent, with Etoposide or RG7388 in Neuroblastoma Cells. (EACR 2026) - "Etoposide has been shown to have a dose-dependent cytotoxic effect on SH-SY5Y cells. Although etoposide has demonstrated ferroptotic potential in different cancers, its ferroptotic potential in SHSY5Y cells could not be triggered by erastin. However, RG7388 showed synergy with erastin and increased cell death in these cells."

Neuroblastoma • Solid Tumor

MDM2 INHIBITION INDUCES AN ADAPTIVE AKT–IDO1 AXIS THAT LIMITS ANTITUMOR EFFICACY IN DIFFUSE LARGE B-CELL LYMPHOMA (EHA 2026) - "Methods DLBCL cell lines harboring wild-type TP53 were treated with the MDM2 inhibitor RG7388...This study provides a mechanistic rationale for combining MDM2 inhibitors with IDO1-targeted immunometabolic therapy to overcome adaptive immune tolerance. Targeting AKT–IDO1 crosstalk may represent a therapeutic vulnerability in DLBCL treated with MDM2-directed agents."

Clinical • IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • IDO1 • MDM2

Genome-Wide CRISPR/Cas9 Screening Identifies Modulators of THZ1 Response in Acute Myeloid Leukemia. (PubMed, Biomedicines) - "THZ1 induced p53 accumulation, and pharmacologic activation of the p53 pathway with idasanutlin further enhanced the early anti-leukemic response to THZ1 at 24 h. TP53 loss reduced the sensitivity of AML cells to THZ1-induced apoptosis, but did not abolish THZ1 responsiveness...THZ1 also continued to suppress these programs in TP53-knockout MOLM-13 cells and TP53-mutant THP-1 cells. Overall, TP53 contributes to the anti-leukemic response to THZ1 but does not determine it, and THZ1 continues to suppress MYC and E2F target programs after TP53 loss."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Long term outcomes of idasanutlin therapy in hydroxyurea-refractory polycythemia vera patients. (PubMed, Leuk Lymphoma) - "Two trials (phase 1/2) of idasanutlin therapy in polycythemia vera patients that were intolerant or refractory to hydroxyurea resulted in substantial clinical and molecular responses. Here the long term outcomes of these patients are reported."

Journal • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

Extrachromosomal MDM2 amplifications define an ecDNA-permissive tumor cell state that impacts intercellular tumor heterogeneity and treatment response across cancers (AACR 2026) - "Whereas chemotherapy rapidly enriched for ecDNA-high cells with reduced TP53 signaling, pharmacologic MDM2 inhibition (Nutlin-3a/Idasanutlin) selectively eliminated ecDNA-high subclones through TP53-dependent apoptosis...Our study demonstrates that MDM2 ecDNA is the predominant ecDNA oncogene in human cancers and defines an ecDNA-permissive state in TP53-wildtype tumors which facilitates rapid adaptation to different therapeutic pressures. These results identify MDM2 ecDNA copy number variation as a functional determinant of acute treatment responses and reveal MDM2-regulated TP53 function as a vulnerability in ecDNA-carrying cancers that may be exploited through rational treatment sequencing."

Heterogeneity • Tumor cell • Astrocytoma • Brain Cancer • Neuroblastoma • Oncology • Solid Tumor • MDM2 • MYCN

Comparative in vivo evaluation of RG-7388, CM-272, and SGI-1027 to determine epigenetic targeting as an effective strategy for treating high-risk neuroblastoma (AACR 2026) - "Epigenetic targeting of DNMT and G9a using CM-272 produced the strongest anti-tumor and survival benefit in the SK-N-AS CDX model, outperforming both RG-7388 and SGI-1027. CM-272's ability to simultaneously inhibit DNMT1 and G9a, appears to reduce repressive chromatin marks, and activate apoptosis cascade that highlights its translational potential for treating TP53-mutant and epigenetically driven neuroblastoma. These initial findings suggest advancing preclinical optimization and combination-therapy strategies involving CM-272 for high-risk neuroblastoma."

Preclinical • Neuroblastoma • Oncology • Solid Tumor • DNMT1

Combination of MDM2 inhibitor and lipophilic gemcitabine: Strong synergism in lung cancer, while antagonism in brain cancer (AACR 2026) - "Combination therapy is therefore recognized as a powerful strategy to enhance therapeutic efficacy and delay resistance.In this study, we investigated the synergistic potential of Idasanutlin (Ida), a second-generation MDM2 inhibitor, and Gemcitabine Elaidate (Gem Eli), a lipophilic prodrug of Gemcitabine, for the treatment of non-small cell lung cancer (NSCLC) and glioblastoma (GBM)...Cryo-electron microscopy confirmed uniform particle morphology with no evidence of aggregation. Ongoing studies are focused on elucidating the cellular mechanisms underlying the observed antagonism in GBM."

Brain Cancer • Glioblastoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

APOBEC4, a novel regulator of p53-dependent tumor suppression (AACR 2026) - "Our findings identify APOBEC4 as a novel regulator of p53-dependent cell cycle arrest, senescence, apoptosis, and tumor suppression, highlighting its potential as a biomarker for p53-targeted therapies."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CDKN1A • GADD45A

Deciphering radiation sensitivity identifies MDM2 as a targetable driver of synergistic radiosensitization in TP53 wild-type lung adenocarcinoma (AACR 2026) - "Our findings demonstrate that MDM2 dependency, revealed through integrative omics analyses, represents a therapeutic vulnerability underlying IR-resistance in p53-proficient LUAD. Combining idasanutlin with radiotherapy effectively overcomes this resistance, highlighting MDM2 as a robust and actionable target for enhancing radiation response in cancers driven by high MDM2 activity."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MDM2 • TP53

Epigenetic modulation by MDM2 and DNMT inhibitor promotes cell cycle arrest and programmed cell death in neuroblastoma cells (AACR 2026) - "To assess the effects of RG-7388, CM-272,and SGI-1027, the neuroblastoma cells were treated for 24 hrs, then qRT-PCR analyses wereconducted to evaluate the gene expressionlevels of DNMT-1, DNMT-3A, DNMT-3B, G9a,EZH2, TET-2, TET-3, MDM2, p53, p21, and PARP...So far, our findingsindicatethatRG-7388, CM-272, and SGI-1027 treatments effectivelydownregulate the expressionofDNMTs, whileupregulatingp21 levels inIMR-32 cells, leadingto cell cycle arrest andapoptosis.The abilityof these experimentalcompounds to inducecell cycle arrest and cell deathsuggests that further evaluationof these compounds could lead to the identificationof apromisingtherapeuticagent for treatingaggressiveneuroblastoma.(Thisprojectwas supported by the NationalPediatricCancer Foundation(NPCF) and The RoyalDames of Cancer Research Inc., Ft. Lauderdale, Florida)"

Neuroblastoma • Oncology • Solid Tumor • BAX • CDKN1A • DNMT1 • DNMT3A • EZH2

Preclinical evaluation of a novel orally bioavailable MDM2 PROTAC, NW-8-461, in acute leukemia and myelofibrosis (AACR 2026) - "NW-8-461 exhibits markedly enhanced antiproliferative activity, demonstrating approximately 10-fold and 100-fold greater potency in cell viability assays compared with RG7388 and AMG232, respectively. In an orthotopic RS4; 11-Luc leukemia model, treatment with NW-8-461 at 25 mg/kg for 16 days resulted in complete eradication of leukemia cells in 7/7 mice and significantly superior efficacy compared with the MDM2 inhibitor RG7388. These results establish NW-8-461 as a differentiated and highly selective MDM2 degrader with strong therapeutic potential for p53-wild-type malignancies."

Late-breaking abstract • Preclinical • Hematological Malignancies • Leukemia • Myelofibrosis • Oncology • GSPT1 • IKZF1 • IKZF3 • MDM2 • SALL4

Discovery of a First-in-Class Murine Double Minute 2-Recruiting Positive Transcription Elongation Factor B PROTAC Degrader With Selective Antitumor Activity. (PubMed, MedComm (2020)) - "To overcome this limitation, we designed a series of highly efficient and selective P-TEFb degraders by conjugating the CDK9 inhibitor SNS032 with the mouse double minute 2 (MDM2) ligand RG7388. Collectively, this study establishes dCDK9-010 as a first-in-class, selective MDM2-recruiting P-TEFb degrader. By enabling the elimination of the entire P-TEFb complex, this MDM2-recruiting degradation strategy expands the toolkit for targeting CDK9 and represents a promising new therapeutic paradigm for TP53 wild-type cancers."

Journal • Preclinical • Ewing Sarcoma • Lung Cancer • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation

Evaluation of the effects of MDM2 inhibitor and epigenetic modifiers in combination with AURKB inhibitors for treating lung cancer (AACR 2025) - "We also examined the anti-cancer effects of RG-7388, SAHA, CM-272, and Barasertib (an AURKB inhibitor), in modulating cell cycle regulation...Our findings confirm that AURKB levels can be down-regulated by using the combination of MDM2 inhibitors and epigenetic regulators such as SAHA and CM-272. However, the therapeutic efficiency of these combinations needs to be verified using in vivo experimental models."

Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALDH1A1 • AURKB • BCL2L1 • CASP7 • CCNA2 • CDC25C • CDK4 • CDK6 • CDKN1A • GNRP • PARP1 • XIAP

A synergy between MDM2 and AURKB pathways in driving cell cycle and cell survival in lung cancer cells (AACR 2024) - "Therefore, the main objective of this study was to understand the molecular mechanisms linking MDM2 and ARKB using RG7388, CM272, BMS-582949 (p38 inhibitor), and Ralimetinib (p38 inhibitor) in A549 and H460 lung cancer cells. (This project was supported by the PFRDG Grant of Nova Southeastern University and by the Generous support from the Royal Dames of Cancer Research Ft. Lauderdale, FL)"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKB • CDK4 • CDKN1A • DNMT1 • DNMT3A • FOXM1 • FOXO3 • GNRP • MDM2 • RASGRF1

Blocking MDM2 induces downregulation of PARP and enhances apoptosis in SK-N-SH neuroblastoma cells (AACR 2025) - "We hypothesize that MDM2 re-activation by the rebound mechanism of RG-7388 induces PARP degradation in SK-N-SH neuroblastoma cells, possibly through a E3 ligase mediated ubiquitination mechanism that is eventually contributing to enhanced apoptosis. To test this hypothesis, SK-N-SH cells were treated with RG-7388 (2 µM), MDM2 specific E3 ligase inhibitor (10 µM), and iRucaparib-AP6 (10 µM), alone or in combination with RG-7388. Our study results indicate that RG-7388 induces significant downregulation of PARP in the SK-N-SH cells, which was leading to enhanced apoptosis. Furthermore, the results of RG-7388 treatment obtained from SK-N-SH cells confirmed its ability to induce cell death through both p53 activation and downregulation of PARP."

Neuroblastoma • Oncology • Solid Tumor • CASP3 • CASP7 • CDKN1A • MDM2 • PARP1

Evaluating the therapeutic potential of MDM2 inhibitor RG-7388 and epigenetic modulator CM-272 in cisplatin-resistant ovarian cancer (AACR 2025) - "Overall, our findings suggest that the MDM2 inhibitor RG-7388 could be a promising therapeutic agent for cisplatin-resistant ovarian cancer, particularly because of its ability to modulateepigenetic regulators like DNMT1. However, the complex interplay between cell survival and epigenetic regulation in drug resistant cells warrant further investigation to optimize the outcomes of combination treatment strategies."

Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • DNMT1 • EZH2 • TP53

Identification of possible new treatment options for rare pediatric CNS tumors using a panel of validated and characterized PDX models (AACR 2024) - "Several targeted agents such as Ipatasertib (AKT inhibitor), Idasanutlin (MDM2-antagonist) and standard of care such as Carboplatin and Radiotherapy induced stable disease as well but had no significant effect on overall survival. The positive results for Vismodegib, Ipatasertib as well as Idasanutlin will be validated in a smaller subset of models in a conventional set-up to confirm the current dataset...CBTRUS statistical report: pediatric brain tumor foundation childhood and adolescent primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro-Oncology (2022) 24(Supplement_3):iii1-38."

Clinical • Brain Cancer • CNS Tumor • Ependymoma • Oncology • Solid Tumor • BCOR • RELA • ZFTA

Efficacy of MDM2 and epigenetic inhibitors treatments for neuroblastoma (AACR 2024) - "In this study, we used selective and reversible small molecule agents such as MDM2 inhibitor (RG7388) and epigenetic modifiers (CM272 and SAHA) to block cell proliferation by inducing cell cycle arrest via enforcing Epigenetic alterations...of Ft. Lauderdale, Florida)"

Clinical • IO biomarker • Neuroblastoma • Oncology • Solid Tumor • AURKB • BAX • BCL2 • CDC25A • CDKN1A • DNMT1 • DNMT3A • DNMT3B • GNRP • RIPK1

Synthesis and evaluation of RG7388-based fluorinated MDM2 inhibitors for developing 18F-labeled probes for PET imaging. (PubMed, Eur J Med Chem) - "[18F]1 showed favorable biodistribution characteristics in healthy mice, and preliminary PET/CT imaging studies revealed a higher uptake of [18F]1 in SJSA-1 xenografts compared to muscle at 1 h post-injection. Western blot analysis of SJSA-1 cells and immunohistochemical staining of SJSA-1 tumor sections confirmed high MDM2 expression and its localization in the nuclei of tumor cells, corroborating the PET imaging data."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • MDM2

Micro RNA level changes in prostate cancer cells treated with MDMX and MDM2 inhibitors (AACR 2024) - "In this regard, several miRNAs were found to be significantly altered to modulate the level and intracellular mechanisms of p53 and MDM2 in various cancers.OBJECTIVES: To determine the relative levels of miRNA31, miRNA-34a and miRNA-128 in LNCaP cells that were treated with NSC-207895 (MDMX inhibitor), SJ-172550 (MDMX inhibitor), and RG-7388 (MDM2 inhibitor). LNCaP cells were treated with NSC-207895 (20 uM), SJ-172550 (20 uM) or RG-7388 (2 uM) for 24 hrs... Our experimental results indicate that inhibition of MDMX using NSC-207895 and SJ-172550 can elevate the levels of p21, p27, and p53 leading to cell death. Determination of cell death markers in the past revealed induction of necroptosis following drug treatments. Our current results indicate measurable changes in the levels of miRNA-31 and miRNA-34a following inhibition of MDMX using SJ-172550."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDKN1A • MIR34A

Genetically characterized canine tumoral cell lines are relevant models to test the efficacy of new targeted therapies: Example of anti-MDM2 targeted therapy (AACR 2025) - "In vivo validation through mouse xenograft modelsAs a proof of concept, we evaluated Idasanutlin, an MDM2 inhibitor, across our developed cell lines...Our genetically characterized cell lines offer a comprehensive platform for drug screening and biomarker discovery, ultimately aiming to improve patient care and survival rates for challenging cancers. This work represents a significant step towards more personalized and precise cancer therapies, bridging the gap between preclinical research and clinical application."

Preclinical • Melanoma • Mucosal Melanoma • Oncology • Sarcoma • Solid Tumor • TP53

Developing a formulation of MDM2 inhibitor: Idasanutlin for enhanced stability, solubility, and anticancer activity in p53 sensitive lung cancer (AACR 2025) - "The observed IC50 of IDA and IDLIN in A549 cells were 3.615µM and 4.766µM respectively and in H460 cells, 0.641µM and 0.707µM was respectively. This is the very first research in use of ionizable lipid in stabilizing anionic hydrophobic molecules and testing nano-formulation of MDMD2 inhibitor in lung cancer."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • MDM2