RG7112 / Roche - LARVOL DELTA

SYNERGIZING MDM2 INHIBITION WITH ANTI-TIM-3 ANTIBODY THERAPY TO ENHANCE THE GRAFT-VERSUS-LEUKEMIA EFFECT (EBMT 2025) - "Doxorubicin, a p53 inducing agent, was used as a positive control.We investigated the impact of anti-TIM-3 Ab and RG7112 on T cell exhaustion and T cell function using in vitro models of T cell exhaustion and cytotoxicity assays. MDM2 inhibition, through RG7112, effectively upregulated TIM-3 ligands in a p53- and dose-dependent way in AML cell lines, suggesting a possible synergistic effect when used in combination with anti-TIM-3 Ab therapy. The combinatory treatment with RG7112 and anti-TIM-3 Ab shows promise in reducing T cell exhaustion. If further confirmed, these findings could provide a rationale for integrating p53-modulating agents with TIM-3 checkpoint blockade in future clinical trials."

IO biomarker • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • CEACAM1 • HMGB1 • LGALS9 • PD-1

SYNERGIZING MDM2 INHIBITION WITH ANTI-TIM-3 ANTIBODY THERAPY TO ENHANCE THE GRAFT-VERSUS-LEUKEMIA EFFECT (EBMT 2025) - "Doxorubicin, a p53 inducing agent, was used as a positive control.We investigated the impact of anti-TIM-3 Ab and RG7112 on T cell exhaustion and T cell function using in vitro models of T cell exhaustion and cytotoxicity assays. MDM2 inhibition, through RG7112, effectively upregulated TIM-3 ligands in a p53- and dose-dependent way in AML cell lines, suggesting a possible synergistic effect when used in combination with anti-TIM-3 Ab therapy. The combinatory treatment with RG7112 and anti-TIM-3 Ab shows promise in reducing T cell exhaustion. If further confirmed, these findings could provide a rationale for integrating p53-modulating agents with TIM-3 checkpoint blockade in future clinical trials."

IO biomarker • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • CEACAM1 • HMGB1 • LGALS9 • PD-1

Senolytic treatment for low back pain. (PubMed, Sci Adv) - "Treatment also lowered degeneration scores in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord. Together, our data suggest RG-7112 and o-vanillin as potential disease-modifying drugs for LBP and other painful disorders linked to cell senescence."

Journal • Back Pain • Lumbar Back Pain • Musculoskeletal Pain • Pain

Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione. (PubMed, J Pharm Anal) - "Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner."

Journal • Liposarcoma • Oncology • Retroperitoneal Sarcoma • Sarcoma • Solid Tumor • SLC7A11

Senolytic compounds reduce epigenetic age of blood samples in vitro. (PubMed, NPJ Aging) - "In this study, we have exemplarily analyzed if a 3-day treatment of human blood samples in vitro would reduce age-associated biomarkers, with a particular focus on epigenetic age-predictions. Of eight tested compounds, JQ1, RG7112, nutlin-3a, and AMG232 reduced epigenetic age, indicating that this approach may be useful in drug screening for senolytic compounds."

Journal • Preclinical

Ezetimibe Anticancer Activity via the p53/Mdm2 Pathway. (PubMed, Biomedicines) - "Thus, Ezetimibe is probably active against cancers that overexpress Mdm2. Moreover, inhibitors of RBBP6 may be combined with Ezetimibe for effective anticancer activity. Due to poor oral bioavailability, Ezetimibe must be administered parenterally for cancer treatment."

Journal • Cardiovascular • Oncology • MDM2 • RBBP6 • TP53

Novel MDM4 Inhibitor CEP-1347-based therapy for p53 wild-type malignant meningioma (SNO 2024) - "The small-molecule MDM2 inhibitor RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. [Conclusion] Our findings suggest that targeting the p53 pathway with CEP-1347 is a novel and viable approach to treating aggressive meningiomas, with even greater efficacy when combined with MDM2 inhibitors."

Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • MDM4

p53 and the E3 Ubiquitin Ligase MDM2 in Glaucomatous Lamina Cribrosa Cells. (PubMed, Int J Mol Sci) - "MTT-assay showed equivocal cellular viability in NLC/GLC cells with/without RG-7112 treatment. Our data suggests that proliferation and the ubiquitin-proteasomal pathway are dysregulated in GLC cells, with MDM2-led p53 protein degradation negatively impacting its protective role."

Journal • Fibrosis • Glaucoma • Immunology • Oncology • Ophthalmology • Targeted Protein Degradation • CASP3 • COL1A1 • MDM2

Assessing the predictive value of genomic drivers for targeted therapy in glioblastoma: Insights from a pre-clinical platform (EORTC-NCI-AACR 2024) - "Representative results from dose-response curves for selected targeted agents in omics-profiled glioblastoma patient-derived models Clinical and molecular information Select driver genomic abnormalitiesMDM2 antagonists dose-reponse AAC values CDK4/6 inhibitors dose-response AAC values Patient ID Age/ Gender Rx prior to surgery OS (days) MGMT promoter Transcriptional Subclass CDKN2A TP53 MDM2 RB1 CDK4 RTK MYC fam. NF1 PTEN RG7112 AMG232 Ribociclib Abemaciclib HF2354 61 M BCNU 196 U undetermined DEL mut NC NC NC NC MYC AMP NC mut 0.05 0.02 0.10 0.08 HF2381 66 M untreated 183 M proneural NC NC AMP NC AMP NC MYC AMP NC 0.61 0.85 0.57 0.75 HF2587 56 F untreated 360 M proneural DEL NC NC NC NC NC NC mut mut 0.68 0.83 0.59 0.60 HF2927 55 F untreated 664 U classical DEL NC NC NC NC EGFR AMP, vIII NC NC DEL 0.52 0.81 0.59 0.67 HF3035 54 F untreated 352 U classical DEL NC NC NC NC MET AMP NC NC DEL 0.44 0.63 0.21 0.28 HF3055 58 M untreated 371 U classical NC NC AMP NC AMP EGFR AMP..."

Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CDKN2A • EGFR • MYCN • NF1 • PDGFRA • PTEN • RB1 • TP53

Association of cellular drug responses and metabolic profiles in adult type diffuse gliomas (EANO 2024) - " First analysis within this cohort (n =18) showed significantly lower AUC values (i.e. enhanced drug response) of panobinostat and vorinostat (HDAC inhibitors), AMG232 and RG7112 (MDM2 inhibitors), selinexor (exportin-1 inhibitor) and temsirolimus (mTOR inhibitor) in IDH-wt gliomas (all p<0.05). These first analyses showed an association between drug response and metabolism when using a holistic approach. Additionally, these results suggested a connection between metabolic pathways and drug susceptibility. In the next step, we plan to investigate the metabolic heterogeneity of IDH-wt gliomas within the tumor in more detail to find out whether there is an influence on the response to treatment."

Clinical • IO biomarker • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • XPO1

HEPATITIS B VIRUS SUBVIRAL PARTICLE BIOGENESIS RELIES ON FUNCTIONAL UBIQUITIN AND PROTEASOME PATHWAYS (AASLD 2024) - "Specifically, the EC50 and CC50 of RG7112 (MDM2 inhibitor), DBeQ (VCP/p97 inhibitor), RA190 (26S proteasome inhibitor), MG-132 (20S proteasome inhibitor) were found to be 10.59μM and >100μM, 10.34μM and 25.89μM, 1.40μM and >50μM, 5.01μM and >100μM, respectively. In summary, our study elucidated that SVP assembly and secretion was regulated by MDM2-ubiquitin-26S proteasome pathway through an unknown host factor other than P53, and further study was supposed to be conducted to identify the unknown host factor, which will provide a theoretical basis for new target on HBV drug discovery."

Hepatitis B • Hepatology • Infectious Disease • Inflammation • Targeted Protein Degradation • ADRM1 • MDM2

Strong activation of p53 by actinomycin D and nutlin-3a overcomes the resistance of cancer cells to the pro-apoptotic activity of the FAS ligand. (PubMed, Apoptosis) - "Interestingly, other combinations of drugs, e.g., etoposide + nutlin-3a, actinomycin D + RG7112, and actinomycin D + idasanutlin had a similar effect. Moreover, normal human fibroblasts are less sensitive to death induced by ActD + Nut3a + FASLG. Our findings create the opportunity to revive the abandoned attempts of cancer immunotherapy employing the recombinant FAS ligand."

Journal • Oncology • CASP10 • CASP8 • CASP9 • FASLG

The Strong Activation of p53 Tumor Suppressor Drives the Synthesis of the Enigmatic Isoform of DUSP13 Protein. (PubMed, Biomedicines) - "We demonstrated for the first time that mRNA expressed from this promoter actually produces the protein, which can be detected with Western blotting, in all examined cancer cell lines with wild-type p53 exposed to A + N. In some cell lines, it is also induced by clinically relevant camptothecin, by nutlin-3a acting alone, or by a combination of actinomycin D and other antagonists of p53-MDM2 interaction-idasanutlin or RG7112. This isoform, fused with green fluorescent protein, localizes in the perinuclear region of cells."

Journal • Oncology • DUSP1 • TP53

MDM2 provides TOP2 poison resistance by promoting proteolysis of TOP2βcc in a p53-independent manner. (PubMed, Cell Death Dis) - "Although the TOP2cc is often transient, stabilization can be achieved by TOP2 poisons, a family of anti-cancer chemotherapeutic agents targeting TOP2, such as etoposide (VP-16), and then induce double-strand breaks (DSBs) in cellular DNA. Furthermore, we demonstrate the combination activity of VP-16 and RG7112, an MDM2 inhibitor, in the xenograft tumor model and in situ lung cancer mouse model. Taken together, the results of our research reveal an underlying mechanism by which MDM2 promotes cancer cell survival in the presence of TOP2 poisons by activating proteolysis of TOP2βcc in a p53-independent manner, and provides a rationale for the combination of MDM2 inhibitors with TOP2 poisons for cancer therapy."

Journal • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Multi-omics joint analysis revealed the metabolic profile of retroperitoneal liposarcoma. (PubMed, Front Med) - "Of particular importance, the glycolytic inhibitor 2-deoxy-D-glucose and pentose phosphate pathway (PPP) inhibitor RRX-001 significantly promoted the antitumor effects of the MDM2 inhibitor RG7112 and CDK4 inhibitor abemaciclib. Our study not only describes the metabolic profiles of RDDLPS and RWDLPS, but also offers potential therapeutic targets and strategies for RLPS."

Journal • Liposarcoma • Oncology • Sarcoma • Solid Tumor

Glioblastoma patient specific transcriptome remodeling in response to MDM2 antagonist treatment of wild-type p53 cancer stem cells is associated with sensitivity and strategies for combination therapy (SNO 2023) - "Seven wt-p53 CSCs were treated RG7112 IC50 concentrations or DMSO control for 24h (n=4)...As validation we found that MDM2a treatment was effective in sensitizing a resistant orthotopic mouse glioblastoma PDX to fractionated RT, with maximum efficacy when treatment started 24h prior to RT vs simultaneously (Log-rank Mantel-Cox test: p=0.0006 vs 0.0277). The integration of the treatment-mediated transcriptional patterns with differential sensibility to MDM2 antagonists and genomic landscape of the CSC panel provides a platform to identify targets for combination therapies, which is the most promising clinical application of the reactivation of wt-p53 in GBMs."

Cancer stem • Clinical • Combination therapy • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells. (PubMed, Cancers (Basel)) - "Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells."

Journal • Tumor cell • Brain Cancer • CNS Tumor • Glioma • Meningioma • Oncology • Solid Tumor • MDM2 • MDM4

Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs. (PubMed, Biomolecules) - "Combining o-Vanillin and RG-7112 greatly enhanced the effect of either senolytic alone. Together, these results support the potential of senolytics as a promising treatment for IVD-related low back pain."

Journal • Back Pain • Endocrine Cancer • Lumbar Back Pain • Musculoskeletal Pain • Neuroendocrine Tumor • Oncology • Pain • Solid Tumor • CASP3

Targeting Apoptosis Pathways in Acute Myeloid Leukemia (SOHO 2019) - P2; "Overall response rate (ORR) was 19% and clinical benefit was observed in 50% of patients.3 Mutations IDH1/2 associated with greater treatment efficacy, whereas mutations in FLT3 and/or PTNP11 associated with primary or secondary resistance to venetoclax.4 In this regard, in a FLT3-mutated AML xenograft mouse model, quizartinib, a FLT3 inhibitor, in combination with venetoclax has shown to produce deeper and more durable responses as compared to single agents.4 Clinical trial studying combinatorial efficacy and safety of venetoclax and quizartinib is currently accruing patients.BH3 profiling showed consistent positive correlation between venetoclax sensitivity and BCL2 dependence, but negative correlation with MCL-1 dependence, encouraging the design of subsequent studies aimed at investigating combination strategies to overcome venetoclax-resistance.2 In this regard, synergistic activity has been reported in pre-clinical AML models when combining venetoclax with..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CALR

Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells. (PubMed, Front Pharmacol) - "Cells were treated with several concentrations of Nutlin-3 or RG-7112, two known MDM2 inhibitors, for the instauration of a cell cycle block steady-state condition before and during SARS-CoV-2 infection, and for the evaluation of p53 activation and impact on virus release and related innate immune events. The results indicated an efficient cell cycle block with inhibition of the virion release and a significant inhibition of IL-6, NF-kB and IFN-λ expression. These data suggest that p53 is an efficient target for new therapies against the virus and that MDM2 inhibitors deserve to be further investigated in this field."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • IL6

Integrated High-Throughput Drug Profiling and CRISPR Screening Identify Novel Pathway Vulnerabilities of Leukemic Stem Cells in Chronic Myeloid Leukemia (ASH 2022) - "Combination of imatinib with idasanutlin, venetoclax, AZD1775 and dexamethasone led to synergistic inhibition of CML-LSCs...We identified specific sensitivity of CML CD34+CD38- cells to mepacrine, RG7112, idasanutlin, and navitoclax...Imatinib, dasatinib, and tivozanib showed a similar profile of resistance and sensitizing genes, while AZD1775 and mepacrine had unique profiles...Furthermore, combination of TKI with deubiquitinase inhibitors induced enhanced TKI sensitivity in KCTD5-KO cells. In conclusion, we discovered novel mechanisms of primary TKI-resistance and drug vulnerabilities of CML-LSCs, which potentially enable eradication of LSCs in CML patients and hence pave the way for the achievement of functional cure in CML patients."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ABL1 • APAF1 • BCR • CD34 • CDK2 • MED23

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

The inhibition of MDM2 slows cell proliferation and activates apoptosis in ADPKD cell lines. (PubMed, Biol Cell) - "Our results indicate that several inflammatory proteins remain aberrantly dysregulated in COVID-19 survivors and CXCL10 might serve as a potential biomarker to typify COV-LH. Further characterization of these signature inflammatory molecules might improve the understanding of the long-term impacts of COVID-19 and provide new targets for the diagnosis and treatment of COVID-19 survivors with PASC."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Polycystic Kidney Disease • CXCL10 • MDM2

Establishment and evaluation of retroperitoneal liposarcoma patient-derived xenograft models: an ideal model for preclinical study. (PubMed, Int J Med Sci) - "Treatment with MDM2 inhibitor RG7112 significantly suppressed tumor growth of DDLPS PDX in mice. In conclusion, we successfully established RLPS PDX models that were histologically, genetically, and molecularly consistent with the original tissues. These models might provide opportunities for advancing RLPS tumor biology research, facilitating the development of novel drugs, particularly those targeting MDM2 amplification, adipose differentiation process, angiogenesis, cancer-associated fibroblasts, and so on."

Journal • Preclinical • Liposarcoma • Obesity • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Transplantation • MDM2

The potential of stem-cell directed therapeutics in myelofibrosis: ONC201 + RG7112 (YouTube) - "Ronald Hoffman, MD, PhD...explains the rationale for developing stem cell-directed therapeutics to treat patients with myeloproliferative neoplasms (MPNs), commenting on the potential of targeting ONC201 with RG7112 in myelofibrosis (MF)....This interview took place virtually."

Interview • Video