Nutlin-3 / EMD Serono - LARVOL DELTA

Development of a lactate metabolism signature for predicting homologous recombination repair status in breast cancer. (PubMed, Sci Rep) - No abstract available

Journal • Breast Cancer • Oncology • Solid Tumor • HRD

Buyang Huanwu Decoction alleviates vascular cognitive impairment by inhibiting neuroinflammation via regulation of the p53/cGAS/STING pathway. (PubMed, J Ethnopharmacol) - "BYHWD ameliorates cognitive deficits and neuropathological damage in 2VO rats primarily through suppression of the p53/cGAS/STING signaling cascade and attenuation of neuroinflammation. This study provides strong pharmacological evidence for the early prevention and clinical treatment of VCI."

Journal • Alzheimer's Disease • Cognitive Disorders • Inflammation

Moonlighting function of the GTP producing enzyme IMPDH2 in melanoma suppression (LCC 2026) - "P53 activation by CX5461, H2O2 or Nutlin-3 led to nuclear translocation of IMPDH2, but this effect was fully abrogated by p53 CRISPR-KO...CDK2 inhibition by INX315 or CDK2 silencing dramatically reduced S122 phosphorylation and induced nuclear translocation of IMPDH2...In contrast, nuclear IMPDH2 acts as a tumour suppressor to repress transcription of E2F target genes and induce CDK inhibitor genes leading to cell cycle arrest and senescence. Increasing IMPDH2's N/C ratio in melanoma cells by targeting its S122 phosphorylation is a promising therapeutic strategy."

Melanoma • Solid Tumor • IMPDH2

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

Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network. (PubMed, Mol Cell) - "Here, we assess how HSF1 activation influences mutational trajectories by which p53 can escape cytotoxic pressure from nutlin-3, an inhibitor of the p53 regulator mouse double minute 2 homolog (MDM2). HSF1 activation broadly increases the fitness of dominant-negative p53 substitutions, particularly non-conservative, biophysically unfavorable amino acid changes within buried regions of the p53 DNA-binding domain. These findings demonstrate that HSF1 activation reshapes the oncogenic mutational landscape by preferentially supporting the emergence and persistence of biophysically disruptive, cancer-associated p53 substitutions, linking proteostasis network activity directly to oncogenic evolution."

Journal • Oncology • HSF1 • TP53

Inhibition of MDM2 by nutlin-3 decreased pyroptosis but increased apoptosis of lung carcinoma cells under 5-FU chemotherapy. (PubMed, J Cancer Res Ther) - "GSDME-mediated pyroptosis plays a pivotal role in chemotherapy-induced cell death in lung adenocarcinoma. MDM2 inhibition, which switches pyroptosis to apoptosis, can be employed to regulate chemotherapy-induced pyroptosis in lung cancer cells and normal tissue cells."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GSDMD • GSDME

Identifying Novel Drug Vulnerabilities in Specified Molecular Subsets of Chronic Lymphocytic Leukemia (ASH 2024) - "Supporting the clinical and biological relevance of our results, venetoclax and ibrutinib were highly effective across CLL, nutlin-3 was ineffective in p53 mutant CLL. Novel drugs with the greatest pan-CLL effects include abexinostat, navitoclax, cerdulatinib, gandotinib and nutlin-3...We found many such associations including high sensitivity of IGHV-mutated CLL (M-CLL) to nutlin-3, IGHV-unmutated CLL (U-CLL) to Onalespib (MWU test, q<0.1), the intermediate epigenetic subtype (i-CLL) to Rapamycin (ANOVA, q<0.1). RNA subtype EC-m4 (TNF- and IFN- high M-CLLs) was specifically sensitive to nutlin-3 and onalespib; and EC-m2 (trisomy 12 enriched M-CLLs) demonstrated resistance to venetoclax and sensitivity to abexinostat (MWU test, p<0.05). Response to lenalidomide was associated with trisomy 12 (MWU, p=0.002)...In summary, we present an experimental strategy to rapidly prioritize novel treatments for CLL patients and a computational framework to inform precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD5 • IGH • TP53

MDM2/p53-based live-cell quantitative FRET imaging for apoptosis drug discovery. (PubMed, Methods) - "In addition, Nutlin-3 treatment decreased the EDmax value in p53 wild-type U2OS cells from 0.43 to 0.20. In summary, our method can identify p53-MDM2 interaction inhibitors in living cells, providing a quantitative in vivo supplement for traditional target-based drug discovery."

Journal • Oncology • BAX

Role of Ras-Related C3 Botulinus Toxin Substrate 1 in p53-Related Proliferation and Drug Sensitivity in Multiple Myeloma (ASH 2024) - "In KMS11/Tet-on p53, KMS26/Tet-on p53, and MM.1S cells, cotreatment with Nutlin-3 and 1A-116 did not increase p53, p21, or Mdm2 protein expression...KMS11 and KMS26 cell survival at 72 h after treatment declined when CRBN modulators lenalidomide, pomalidomide, and iberdomide were combined with the Rac1 inhibitor 1A-116 (25µM) compared with CRBN modulator treatment alone. In contrast, Rac1 inhibitor showed no additive effect on cell survival after 24 h of bortezomib treatment in HMCLs...High RAC1 mRNA expression in intramedullary plasma cells of patients with NDMM is associated with worse prognosis. Our research provides new insights for development of novel therapies targeting the Rac1 pathway to improve MM patient prognosis, including patients with p53 dysfunction."

Hematological Malignancies • Lymphoma • Monoclonal Gammopathy • Multiple Myeloma • Oncology • ANXA5 • CDC42 • CDKN1A • CRBN • MDM2 • RHOA • SDC1

Aberrant Stemness Transcription Signature Unveils a Mechanism of Chemotherapy Resistance through Blunting p53-Mediated Response in Acute Myeloid Leukemia (ASH 2024) - "Deletion of Gata2 in Gata2 high cells increased activation of p53-mediated apoptosis in response to nutlin-3...We evaluated whether MDM2 inhibitors, such as Idasanutlin, in combination with doxorubicin, could overcome the drug resistance seen in Gata2high leukemias...Our study supports a model where the "volume control" of p53-mediated apoptosis by a stem cell transcription factor is an integral part of stemness, which is imparted on leukemic cells arising from a stem-cell-like cell-of-origin. Our findings provide a mechanistic explanation for the well-established, but thus far unexplained observation that the expression of HSC signatures are associated with poor outcomes in AML."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Pediatrics • GATA2 • KMT2A • MECOM • MLLT3

Targeting STAU1 prevents p53 apoptotic signaling in neurodegeneration. (PubMed, Cell Death Dis) - "In both proliferating and post-mitotic cell types-human iPSC-derived neurons, mouse cortical neurons, SH-SY5Y cells, and fibroblasts-STAU1 reduction effectively prevented p53-mediated apoptosis and DNA damage induced by Nutlin-3 and etoposide. Further examination in C9orf72-expanded patient-derived fibroblasts and a C9orf72 mouse model of ALS/FTD, which exhibit baseline overabundance of STAU1 and activation of the p53 pathway, confirmed that STAU1 reduction also prevented p53-driven pro-apoptotic signaling. These findings establish STAU1 as a novel modulator of DNA damage and p53-dependent apoptosis, suggesting that targeting STAU1 could be a promising approach to prevent neurodegeneration in ALS/FTD."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • Ataxia • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Movement Disorders

p53 regulates glucose metabolic reprogramming in MASLD-related hepatocellular carcinoma via modulating mitochondrial pyruvate carriers. (PubMed, Hepatol Int) - "TP53 drives metabolic reprogramming in MASLD-HCC via the PUMA-MPC axis, promoting glycolysis-dependent tumor progression. This challenges the conventional tumor-suppressive role of p53, highlighting its context-dependent pro-tumorigenic function under metabolic stress. Targeting the p53-PUMA-MPC pathway may provide potential targets for precision therapy."

Journal • Hepatocellular Cancer • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor

CHOLESTEROL SYNTHESIS DYSREGULATION PROMOTES COLORECTAL TUMORIGENESIS VIA UPREGULATING CNPY3 TO ENHANCE MDM2 NUCLEAR TRANSLOCATION (UEGW 2025) - "Simvastatin, Fatostain, and Nutlin-3 all reversed the CRC tumorigenesis induced by CNPY3. This work ligates cholesterol reprogramming ligation to p53 inactivation in CRC by SREBP2-CNPY3-p53 axis. CNPY3 could be used both as a prognostic biomarker and as a therapeutic target, with a combination of statins/Nutlin-3 regimens, showing promise for novel treatments for CRC. Our findings redefine lipid metabolism as an epigenetic driver of loss of tumor suppression, providing a new strategy for metabolically stratified therapies."

Colon Cancer • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • MDM2 • TP53 • TRIM21

Exendin-4 improves mitochondrial integrity against cisplatin-induced cardiac damage: Targeting p53 and NF-κB pathways. (PubMed, Eur J Pharmacol) - "Heart failure is a devastating consequence of chemotherapy, with mitochondrial dysfunction playing a key role in cardiac damage. Pharmacological inhibition of p53 (pifithrin-α) or NF-κB (JSH-23) further amplified the protective effect of Ex-4 against CP-induced mitochondrial abnormalities, apoptosis, and inflammation, whereas activation of p53 (nutlin-3) or NF-κB (NF-κB activator 1) reversed these protective outcomes. Thus, Ex-4 emerges as a potent modulator of mitochondrial dysfunction and cellular stress through suppression of the p53 and NF-κB pathways, offering a promising therapeutic approach to mitigate CP-induced cardiotoxicity."

IO biomarker • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • Metabolic Disorders • BAX • BCL2 • CASP3 • CASP7 • IL6 • MFN1 • NRF1 • TNFA

DNA-hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation. (PubMed, J Pathol) - "Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway."

Journal • Epstein-Barr Virus Infections • Gastric Cancer • Microsatellite Instability • Oncology • Solid Tumor • MDM2 • MLH1 • MSI

ACTIVATION OF A TUMOR SUPPRESSOR P53 DRIVES ACUTE LIVER FAILURE VIA UPREGULATION OF LEUKEMIA INHIBITORY FACTOR (LIF) (AASLD 2025) - " We used genetically modified mice including hepatocyte-specific Mdm2-deficient mice (Alb-CreER Mdm2fl/fl + Tamoxifen: Mdm2ΔHep mice), Mdm2 and p53 double-deficient mice (Alb-CreER Mdm2fl/fl p53fl/fl + Tamoxifen), and LIF-deficient mice (LIF+/-)...In HepG2 and CL2 cells, treatment with a Mdm2 inhibitor Nutlin-3 increased LIF expression, while p53 knockdown suppressed it, indicating that LIF is regulated downstream of p53 in hepatocytes... p53 activation in hepatocytes drives ALF via LIF-mediated liver injury. Targeting p53-LIF axis may offer a novel therapeutic approach for ALF."

Hematological Malignancies • Hepatology • Inflammation • Leukemia • Liver Failure • Oncology • CDKN1A • ITGAM • LIF • MDM2 • TP53

Epigenetically regulated p53 activity maintains intestinal regulatory T cell identity to prevent inflammation. (PubMed, bioRxiv) - "Stabilization of p53 using the MDM2 inhibitor Nutlin-3 protected Tregs from losing their master transcription factor Foxp3 in vitro when cultured with the Th17 cytokines IL-6 and IL-1β, while p53 deficiency rendered Tregs more prone to Foxp3 loss...Additionally, these mice exhibited inflammation in the colon at homeostasis and increased severity of induced colitis. These results demonstrate a specific role for p53 in the maintenance of Treg stability in Th17-polarizing environments and present a possible target for improving Treg-based immunotherapies for diseases defined by intestinal inflammation, such as inflammatory bowel disease (IBD)."

IO biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • FOXP3 • IL1B • IL6 • TP53

Functional analysis of in-frame variants in TP53 gene identified in adult leukemias: A study of the TP53 Network of European Research Initiative on CLL (IWCLL 2025) - "Selected variants were further tested in RPE1 TP53-knockout human cells expressing doxycyclin-inducible p53 variants, with functional assessment via nutlin-3 stabilization and measurement of endogenous MDM2 and p21 proteins and BAX mRNA levels. Sixty cDNA samples containing in-frame TP53 variants previously detected by routine gene sequencing in chronic lymphocytic leukemia (CLL; 88%) or other hematological malignancies were collected from 13 ERIC centers... All 49 in-frame TP53 variants located within the core region of the DNA-binding domain resulted in a loss of transactivation function, while the variants downstream of codon 287 displayed heterogeneous phenotypes depending on testing system and localization, with variants located in OD being predominantly non-functional. Our findings support the interpretation that in-frame TP53 variants within the core DBD region are likely pathogenic when identified in tumor samples. In contrast, interpretation of in-frame variants..."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • CCNI • CDKN1A • PAICS • TP53

In-frame germline TP53 variant impairs p53 oligomerization and predisposes to cancer. (PubMed, Sci Rep) - "Finally, we found that cells expressing the p.E339_F341del variant were insensitive to inhibition of MDM2 by nutlin-3 confirming the functional defect. We conclude that the in-frame germline c.1015_1023del TP53 variant encodes a transcriptionally inactive protein and promotes LFS with a high penetrant cancer phenotype."

Journal • Adrenal Cortex Carcinoma • Breast Cancer • Genito-urinary Cancer • Metabolic Disorders • Oncology • Sarcoma • Solid Tumor • TP53

Anticancer effects and mechanisms of Pulsatilla chinensis, Bupleurum chinense and Polyporus umbellatus on human lung carcinoma and hepatoma cells. (PubMed, Comput Struct Biotechnol J) - "We also identified two drugs, AMG232 and Nutlin-3, that exhibited treatment effects similar to P. chinensis in A549 cells. Western blot analysis confirmed the alteration of the relevant proteins, aligning with our computational predictions. Furthermore, 23-hydroxybetulinic acid, a key active compound of P. chinensis, demonstrated the ability to inhibit the p53-MDM2 interaction by binding to the same pocket on the MDM2 protein."

Journal • Hepatocellular Cancer • Liver Cancer • Lung Cancer • Oncology • Solid Tumor • E2F1 • TNFA

Transcription Factors and Methods for the Pharmacological Correction of Their Activity. (PubMed, Int J Mol Sci) - "p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat...AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK...Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential."

Journal • Review • CNS Disorders • Hematological Disorders • Immunology • Oncology • Rheumatology • Targeted Protein Degradation • HIF1A • STAT3 • STAT5 • STAT5AWqe

p53 enhances elesclomol-Cu-induced cuproptosis in hepatocellular carcinoma via FDXR-mediated FDX1 upregulation. (PubMed, Front Oncol) - "p53 overexpression/knockdown, siRNA-mediated ferredoxin reductase (FDXR)/FDX1 knockdown, and the p53 activators CP-31398 and nutlin-3 were employed to elucidate the associated molecular mechanisms. These findings revealed that p53 enhances elesclomol-Cu-induced cuproptosis in HCC via FDXR-mediated FDX1 upregulation. This study provides mechanistic insights into p53's role in cuproptosis and may serve as a basis for targeting copper metabolism in therapeutic strategies for HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • DLAT • FDX1 • FDXR

Paeoniflorin mitigates iron overload-induced osteoarthritis by suppressing chondrocyte ferroptosis via the p53/SLC7A11/GPX4 pathway. (PubMed, Int Immunopharmacol) - "PAE alleviates iron overload-induced OA progression by inhibiting ferroptosis through regulation of the p53/SLC7A11/GPX4 pathway, offering new insights into ferroptosis-targeted OA therapy."

Journal • Hematological Disorders • Immunology • Osteoarthritis • Osteoporosis • Pain • Rheumatology • GPX4 • MMP13 • SLC7A11

Potentiation of AKR1C3- and P53-dependent AST-3424 activity via PUMA-mediated degradation of Rad51 (AACR 2025) - "Co-treatment with AST-3424 and the P53 activator nutlin-3 significantly potentiated AST-3424's pharmacological activities, including in vitro cytotoxicity, reduced colony formation, apoptosis induction, DNA damage (γH2AX), and G2/M phase cell cycle arrest. We elucidate the mechanism of tumor-specific enhancement associated with P53-dependent RAD51 degradation, leading to decreased homology-directed DNA repair and synthetic lethality. These insights have significant implications for optimizing AST-3424's antitumor efficacy and potentially improving survival rates in patients with functional P53."

IO biomarker • Hematological Malignancies • Liver Cancer • Oncology • AKR1C3 • HRD • RAD51

ATM and p53 in aging and cancer: a double-edged sword in genomic integrity. (PubMed, Biogerontology) - "Chemical small molecule p53 activators (PRIMA-1, Nutlin-3) and ATM inhibitors (AZD0156, M4076) sensitize cancer to DNA damaging therapy in cells and nude mice without p53. In this review, we consolidate state-of-the-art findings on ATM and p53 coordination in the processes involved in DNA repair, apoptosis, and senescence to show how ATM and p53 dual involvement in tumor suppression and cancer progression is occurring. It also focuses on therapeutic approaches targeting these pathways to benefit from senescence and intimidating cancer treatment outcomes."

Journal • Review • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency