Nutlin-3 / EMD Serono - LARVOL DELTA

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

Hijacking the MDM2 E3 Ligase with novel BRD4-Targeting PROTACs in Pancreatic Cancer Cells. (PubMed, Chembiochem) - "Here we report the discovery of novel MDM2-recruiting PROTACs incorporating rac-Nutlin-3 as a ligand with an easier synthetic tractability, further demonstrating its potential in this technology. The most promising degrader, PROTAC 3, showed preferential degradation of the BRD4 short isoform and c-Myc compared with MZ1, a validated VHL-based PROTAC."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • BRD4 • CRBN • MYC • TP53

Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma. (PubMed, Oncol Lett) - "Nutlin-3 combined with erastin or RSL3 reduced absolute p-4EBP-1 levels in NDDLS-1 cells and p-p70S6 levels in both cell lines, with no significant impact on the p-4EBP-1/4EBP-1 and p-p70S6/p70S6 ratios. These results indicate that ferroptosis is a therapeutic vulnerability in the response to MDM2 inhibition in DDLPS. Furthermore, combining MDM2 inhibitors with ferroptosis-inducing agents may provide a potential therapeutic strategy for DDLPS and the role of mTOR in the pro-apoptotic effect of these combinations deserve further investigation."

Journal • Liposarcoma • Oncology • Sarcoma • Solid Tumor • GPX4 • SLC3A2 • SLC7A11

O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells. (PubMed, J Am Chem Soc) - "Leveraging a structure-based drug design, we incorporated CNBA into the core structure of Nutlin-3 to irreversibly inhibit the MDM2-p53 interaction by targeting an exposed lysine K94 on the surface of murine double minute 2. Importantly, we have demonstrated the potential application of CNBA as a lysine-recognized bioconjugation agent for developing new antibody-drug conjugates. The results collectively validate CNBA as a new selective and efficient modifying agent with broad applications for both buried and exposed lysine residues in live cells."

Journal

Development of MDM2-Targeting PROTAC for Advancing Bone Regeneration. (PubMed, Adv Sci (Weinh)) - "An MDM2-PROTAC library is constructed by combining Nutlin-3 and CRBN ligands with various linker designs. In the OVX model, the combination treatment with CL144 and alendronate induced a synergistic effect. Overall, this study demonstrates the promising role of MDM2-PROTAC in promoting bone regeneration, marking the first step toward expanding the application of the PROTAC technology."

Journal • Osteoporosis • Rheumatology • Targeted Protein Degradation • CRBN

MAGL targeted PROTAC degrader simultaneously enhances P53 for synergistic treatment of glioblastoma stem cell. (PubMed, Cell Death Discov) - "Then the PROTAC was conjugated with JZL184 analog and the MDM2 inhibitor Nutlin-3 analog. Experimental results validated that the designed JN-PROTAC effectively induced MAGL targeted degradation and concomitantly enhanced P53 activation via MDM2 inhibition and is capable of inhibiting the progression of patient-derived GSCs in vivo. This work presents a proof-of-concept PROTAC design tailored for GSCs, potentially addressing the occurrence challenges for GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • TP53

PP2A adapter protein IER5 induces dephosphorylation and degradation of MDM2, thereby stabilizing p53. (PubMed, Cell Signal) - "Importantly, IER5 fails to inhibit p53 ubiquitination in cells treated with the MDM2 inhibitor Nutlin-3. The IER5-PP2A/B55 complex dephosphorylates MDM2 at Ser166, leading to MDM2 ubiquitination and a reduction in nuclear MDM2. Altogether, our data provide evidence that IER5-PP2A/B55 regulates the nuclear balance between MDM2 and p53 via MDM2 dephosphorylation."

Journal • Oncology • Targeted Protein Degradation