Nutlin-3 / EMD Serono - LARVOL DELTA

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

LncDNAH5 Regulates Radiotherapy-Induced Toxicity via MDM2-Mediated Degradation of TP53BP1. (PubMed, Int J Radiat Oncol Biol Phys) - "Mechanistically, LncDNAH5 enhanced MDM2-dependent ubiquitination and degradation of TP53BP1 by promoting formation of an MDM2-TP53BP1 complex; MDM2 antagonist Nutlin-3 attenuated these effects...Together, these data support a rs7720298/LncDNAH5/MDM2/TP53BP1 axis that modulates DNA repair choice and tissue response to radiation. Clinically, LncDNAH5 expression and rs7720298 genotype may serve as complementary biomarkers to identify patients at risk for late urinary toxicity and to guide early intervention and personalized radioprotective strategies for better patient outcomes."

Journal • Fibrosis • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • TP53BP1

Gastrodin alleviates hypobaric hypoxia-induced brain injury in rats by reducing neuronal ferroptosis via the P53/SLC7A11/GPX4 signaling axis (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "GAS produces neuroprotective effects against HH-induced brain injury in rats by inhibiting neuronal ferroptosis via regulating the P53/SLC7A11/GPX4 signaling pathway."

Journal • Preclinical • CNS Disorders • Vascular Neurology • GPX4 • SLC7A11

Compound delivery of eVLPs enhances prime editing for targeted genome engineering and high-throughput screening. (PubMed, Cell Genom) - "Using a 6,000-pegRNA library targeting TP53, PRIME-VLP achieved 2.8-fold higher editing and improved reproducibility compared to conventional lentiviral delivery, identifying TP53 loss-of-function variants conferring Nutlin-3 resistance. This work expands the versatility of eVLPs beyond their current in vivo therapeutic applications, demonstrating their promise for high-throughput functional genomics."

Journal • Infectious Disease • TP53

Epigenetic control of p53 activity in regulatory T cells maintains their identity to prevent inflammation. (PubMed, J Immunol) - "Stabilization of p53 using the MDM2 inhibitor Nutlin-3 protected Tregs from losing their master transcription factor FOXP3 in vitro when cultured with the T helper 17 cytokines interleukin-6 and interleukin-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 inflammatory T helper 17-polarizing environments and present a possible target for improving Treg-based immunotherapies for diseases defined by intestinal inflammation, such as inflammatory bowel disease."

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

Adenovirus mediated gene therapy in cell lines derived from canine oral melanoma. (PubMed, Front Immunol) - "These cell lines harbor wild-type p53, which, in response to treatment with doxorubicin or Nutlin-3, promoted the expression of well-known p53 target genes (CDKN1A, MDM2). Treatment with adenoviral vectors encoding canine p14ARF and interferon-β (IFNβ) resulted in cell death with liberation of immunogenic cell death markers in vitro and reduction of tumor progression when subcutaneous tumors in nude mice were treated with in situ gene therapy. These results indicate that adenovirus-mediated delivery of p14ARF and IFNβ is effective in a canine model of oral melanoma, supporting the feasibility of applying comparative oncology approaches to the development of this gene therapy strategy."

Journal • Preclinical • Gene Therapies • Melanoma • Oncology • Solid Tumor • CDKN1A • CDKN2A • IFNB1 • TP53

Baicalin executes anticancer property via inhibition of MDM2-p53 interaction: a mechanistic study using in silico approach. (PubMed, J Biomol Struct Dyn) - "Molecular docking predicted a binding affinity of -7.1 kcal/mol, with baicalin occupying the p53-binding pocket of MDM2, whereas the known inhibitor Nutlin-3 showed a docking-predicted binding energy of -7.5 kcal/mol...In vitro assays showed that baicalin inhibited proliferation and induced morphological changes more prominently in MCF-7 cells compared to MDA-MB-231 cells, supporting a possible p53-dependent response. Overall, this study provides computational and preliminary cellular evidence that baicalin may interact with MDM2 and contribute to p53-mediated anticancer activity."

Journal • Oncology • TP53

SREBP2-activated CNPY3 Phase Separation Promotes Colorectal Cancer by Enhancing MDM2-mediated p53 Degradation. (PubMed, Int J Biol Sci) - "Pharmacological disruption of the MDM2-p53 interaction with Nutlin-3 effectively reversed CNPY3-driven malignancy both in vitro and in vivo...We further established that the oncogenic activity of CNPY3 is mediated through its biophysical property of LLPS. These findings nominate CNPY3 as a novel prognostic biomarker and a compelling therapeutic target for p53-wild-type CRC."

Journal • Colorectal Cancer • Dyslipidemia • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation

Mechanosensitive ion channel TRPV4 inhibition alleviates glaucomatous inflammation by regulating microglial ferroptosis. (PubMed, Int Immunopharmacol) - "The function of TRPV4 was validated using the specific inhibitor HC-067047 and TRPV4 gene knockdown, and the p53/SLC7A11/GPX4 ferroptosis axis was investigated using the ferroptosis inhibitor Ferrostatin-1 (Fer-1), the p53 agonist Nutlin-3, and p53 gene knockdown...Notably, pharmacological inhibition of TRPV4 reversed these responses, shifting microglia toward an anti-inflammatory M2 phenotype and mitigating ganglion cell loss. These findings demonstrate that TRPV4 activation drives ferroptosis via the p53/SLC7A11/GPX4 axis, thereby promoting microglial-mediated neuroinflammation, providing a new theoretical perspective for understanding the pathogenesis of neuroinflamation in glaucoma."

Journal • Cardiovascular • CNS Disorders • Glaucoma • Inflammation • Ocular Inflammation • Ophthalmology • GPX4 • SLC7A11 • TRPV4

Exploring the role of MDM2-TP53 pathway and ATM in regulation of ferroptosis in dedifferentiated liposarcoma (AACR 2024) - "In our previous study, we had showed that nutlin-3, a MDM2 inhibitor, could exert synergistic cytotoxicity with ferroptosis-inducing agent (erastin and RSL3) on DDLPS in a sequential manner, possibly through upregulation of SLC3A2 with altered cystine/glutamate exchange (AACR Annual Meeting 2023 abstract#4777). Modulation of ferroptosis is a potential treatment strategy in DDLPS. MDM2-TP53 pathway and ATM as well as interaction of both may play an important role in regulation of ferroptosis in DDLPS. Combination of DDA, such as cisplatin, and ferroptosis-inducing agents is a potential strategy in DDLPS treatment."

Liposarcoma • Oncology • Sarcoma • Solid Tumor • SLC3A2 • 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

Unlocking the Anticancer Potential of New Spirooxindoles via p53-MDM2/MDMX Dual Inhibition: In Vitro and In Silico Assessments. (PubMed, Drug Dev Res) - "The spirooxindoles 6b, 6k, and 6n attained the most pronounced activity in the MULTI-ARRAY MDM2-p53 complex assay with IC50 values of 1.26, 1.30, and 1.25 µM, respectively, in comparison with nutlin-3 (IC50 = 2.03 µM)...Molecular docking and molecular dynamics simulations justified the observed efficacy. Collectively, this study showcased a new class of potent p53-MDM2/MDMX dual inhibitors possessing a spirooxindole scaffold which can be subjected to future development."

Journal • Preclinical • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • MDM2

Formononetin downregulates P53/SAT1/ACSL4 pathway-mediated ferroptosis to improve hypoxic-ischemic brain injury in neonatal mice (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "FMN produces neuro-protective effects against HIBD in neonatal mice by mitigating neuronal ferroptosis, primarily through downregulation of the P53/SAT1/ACSL4 signaling pathway."

Journal • Preclinical • CNS Disorders • Vascular Neurology • ACSL4 • SAT1 • TP53

Tracing tumor evolution in pulmonary neuroendocrine cancer using patient-derived tumor organoids (ENETS 2026) - "TP53-edited cells showed clonal expansion, increased proliferation, and survival under nutlin-3, consistent with TP53 loss. RB1-edited and dou - ble-knockout lines continued proliferating under palbociclib, validating RB1 inactivation... Loss of TP53 and RB1 promotes proliferation in pul - monary neuroendocrine tumors and may facilitate evolution to - ward NEC-like states accompanied by altered growth-factor de - pendence. This organoid platform enables controlled modeling of neuroendocrine tumor progression and supports identification of vulnerabilities in aggressive disease."

Clinical • Endocrine Cancer • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Solid Tumor • EGF • NF1 • PI3K • RB1

Targeting the Xylosyltransferase TMEM5 in Glioblastoma to Modulate CLOCK and CRY1 Expression and Restore Temozolomide Sensitivity via the Circadian Signaling Axis. (PubMed, Eur J Pharm Sci) - "TMEM5 is associated with circadian-gene expression patterns, temozolomide response, and bioenergetic readouts in GBM models. TMEM5 knockdown was accompanied by altered time-dependent expression profiles of multiple clock genes, reduced OCR/ECAR parameters under the tested conditions, and increased TMZ sensitivity. These findings support TMEM5 as a circadian-associated factor in GBM and provide a rationale for future studies to define whether TMEM5 directly influences circadian regulation and metabolic pathway remodeling in vivo."

Journal • Brain Cancer • Glioblastoma • Oncology • Sleep Disorder • Solid Tumor • ARNTL • BMAL1 • CLOCK • CRY1 • PER1 • PER2

Isoquercitrin Attenuates Osteoarthritis Progression by Targeting P53-Mediated Ferroptosis: A Mechanistic Study Integrating Network Pharmacology and Experimental Validation. (PubMed, J Nutr Biochem) - "Notably, these protective effects were partially reversed upon co-treatment with nutlin-3, a pharmacological activator of P53. Collectively, these findings demonstrate that ISO alleviates OA pathology by inhibiting P53-dependent ferroptosis, highlighting its potential as a dietary supplement for the prevention and management of OA."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • ADAMTS5 • COL2A1 • GPX4 • MMP13 • SLC7A11

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

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