eprenetapopt (APR-246) / Aprea - LARVOL DELTA

Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes. (PubMed, J Clin Oncol) - P2 | "In patients with mTP53 AML and MDS, post-HCT maintenance therapy with eprenetapopt combined with azacitidine was well tolerated. RFS and OS outcomes were encouraging in this high-risk population."

Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion study. (PubMed, Lancet Haematol) - P1 | "Eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia."

Journal • P1 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Leukopenia • Myelodysplastic Syndrome • Neutropenia • Oncology • Septic Shock • Thrombocytopenia • TP53

Study of the Safety and Efficacy of APR-246 in Combination With Azacitidine (clinicaltrials.gov) - P1/2 | N=53 | Completed | Sponsor: Groupe Francophone des Myelodysplasies | Unknown status ➔ Completed | Phase classification: P1b/2 ➔ P1/2

Phase classification • Trial completion • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • TP53

APR-246 and TKI Resensitize a Specific TP53-Mutant NSCLC Subpopulation (IASLC-WCLC 2026) - "Conclusions : We define a novel, structurally precise therapeutic window for p53 reactivation in NSCLC. By demonstrating that specific cryptic pockets (Pocket 1/2/3) dictate drug sensitivity, and uncovering EMT/Hypoxia as key resistance bypasses, this PDO-AI platform provides a robust, data-driven rationale for "structure-guided" patient selection, rescuing TKI efficacy in the most refractory subset of TP53 -mutant lung cancer."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ALK • CDKN1A • EGFR • HIF1A • ROS1 • TP53

Genomic and transcriptomic landscape of TP53 alterations in pediatric high-grade gliomas (EANO 2026) - "TP53 alterations play a central role in pHGG biology and clinical outcome, with distinct differences compared to adult gliomas. A higher proportion of truncating mutations in pediatric tumors suggests differences in TP53 functional inactivation. Notably, mutation-specific agents such as Rezatapopt, targeting the Y220C variant, may have limited applicability as this alteration was not observed in our cohort, while the modest clinical benefit observed with Eprenetapopt highlights the need for mutation-informed and age-specific therapeutic strategies."

Clinical • Tumor mutational burden • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • ATRX • H3-3A • PDGFRA • TMB • TP53

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies. (PubMed, Bull Cancer) - "Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • AURKB • CHEK1 • HER-2 • TP53

Randomized Treatments for Myelodysplastic Syndrome and Related Disorders: A Comprehensive Component Network Meta-Analysis of Randomized Controlled Trials (SOHO 2026) - "Compared with best supportive care, higher odds of complete remission were observed for azacitidine, azacitidine plus lenalidomide, azacitidine plus vorinostat, panobinostat plus azacitidine, APR-246 plus azacitidine, decitabine, decitabine plus valproic acid, and glasdegib plus cytarabine. This review combines broad trial identification, structured screening, detailed extraction, and treatment level synthesis across a complex therapeutic landscape. Its findings may support future guidelines, whereas the contrast between regimen- and component-level effects leaves key clinical questions for the full review to resolve."

Retrospective data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

The impact of TP53 mutations and use of the TP53-mutation-reactivating agent APR-246 on metastatic castrate-sensitive prostate cancer. (ASCO 2023) - "DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro, which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies."

Metastases • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • TP53

Identifying cysteine-reactive probes to stabilize p53 mutants | Poster Board #1017 (ACS-Fall 2026) - "Small molecules such as PRIMA-1 and its methylated analogue APR-246 have demonstrated the ability to restore wild-type p53 function...This project aims to develop a library of MQ derivatives capable of selectively restoring mutant p53 DNA-binding activity. Using proteome-wide reactivity profiling, mass spectrometry, in vitro biochemical assays, and DNA gel-based binding studies, we will evaluate the selectivity, on- and off-target interactions, and functional reactivation potential of MQ derivatives in cancer cells."

P53mut • Targeted Protein Degradation • CDKN1A • DDB2 • TP53

Functional restoration of conformational (R175H) and contact (R273H) mutant p53 by Bacillus-derived Hydroxymycotrienin A in non-small cell lung cancer: a computational approach. (PubMed, Front Bioinform) - "Current strategies, using the covalent binder APR-246, are limited by off-target toxicity and resistance...By restoring p53 function, this study addresses Sustainable Development Goals Target 3.4 to reduce premature mortality from non-communicable diseases. However, future in vitro and in vivo studies are required to validate the efficacy of these compounds."

Journal • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TP53

Fundamentals and emerging frontiers in p53-targeted drug development. (PubMed, Biochem Biophys Rep) - "It elaborates on the structure and function of p53 and its mutation-induced carcinogenic mechanisms, then focuses on analyzing the research history and clinical translation status of small-molecule drugs (e.g., APR-246), discusses the application prospects of gene therapy and immunotherapy strategies, and introduces emerging therapies based on CRISPR and PROTAC technologies. By integrating the latest research findings, this article aims to provide theoretical basis and directional guidance for the precise development and clinical translation of p53-targeted drugs."

IO biomarker • Journal • Review • Gene Therapies • Oncology • Targeted Protein Degradation • TP53

ATP5E LACTYLATION MEDIATED BY TP53 MUTATION PROMOTES PROGRESSION OF DIFFUSE LARGE B-CELL LYMPHOMA (EHA 2026) - "Knocking down mutant TP53 doesn't affect the cell cycle but reduces LDHA expression, lactate levels, and APR-246 sensitivity...Summary/Conclusion MUT-TP53 creates a lactate-lactylation pathway in DLBCL by increasing LDHA/lactate and promoting ATP5E K44la, which stabilizes ATP5E, boosts mitochondrial remodeling, and supports tumor growth. This highlights lactate metabolism, lactylation, ATP5E K44la, and mutant-p53 as potential therapeutic targets."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • ATP5F1E • LDHA • TP53

HOTSPOT GENE MUTATIONS AND TREATMENT RESPONSE IN MYELODYSPLASTIC SYNDROMES (MDS): PREDICTIVE BIOMARKERS AND TARGETED STRATEGIES (EHA 2026) - "Results HMAs:ASXL1mut → HMA resistance (ORR 32 %), but VEN+HMA rescue (ORR 87 %); TET2mut/ASXL1wt → best HMA response (ORR 62 %); dual TET2-ASXL1 loses benefit (19 %); DNMT3A-R882 decitabine hypersensitivity via hemi-methylated enhancer trapping; median PFS 20.3 vs 50 mo WT; Chemotherapy:RUNX1, BCOR, EZH2 mutations independently cut response to cytarabine/anthracycline (ORR ≤19 %); Targeted therapyTP53 multi-hit: eprenetapopt + AZA ORR 73 %, median OS not reached at 12 mo; IDH1/2 mut: ivosidenib 83 % ORR, mOS 35.7 mo; enasidenib 53 % ORR, mOS 16.9 mo. Summary/Conclusion ASXL1, TET2, DNMT3A, RUNX1, BCOR, EZH2, TP53, IDH1/2 mutations are actionable predictors; genotyping should guide front-line therapy and trial selection."

Biomarker • Hematological Malignancies • Immunology • Myelodysplastic Syndrome • ASXL1 • BCOR • DNMT3A • IDH1 • IDH2 • RUNX1 • TET2 • TP53

Unveiling Candidate Markers for Drug Resistance or Synthetic Lethality in Cervical Cancer: Integrative Analysis of Genetic and Pharmacoprofiling. (PubMed, Cancer Rep (Hoboken)) - "This paper reports genetic variants in 20 CLs as well as the results of the assessment on whether those variants may help predict response or resistance to certain drug families. With a few exceptions, genetic alteration frequency in CCCLs, conducted in the same analytical batches, compares favorably with published patient data. Results need confirmation in independent larger studies both in CLs and in clinical settings."

Journal • Cervical Cancer • Oncology • Solid Tumor • ALPK2 • CLDN1 • CSMD3 • NBPF1 • NLRP1 • OSBPL1A • STK11

Wild-Type p53 Protein Enhances APR-246-Induced Cytotoxicity in Acute Myeloid Leukemia and Normal Hematopoietic Stem/Progenitor Cells. (PubMed, Int J Mol Sci) - "Mechanistically, the loss of functional p53 proteins in Molm13 and MV4-11 cells decreased intrinsic apoptosis and impaired the production of cellular reactive oxygen species (ROS) induced by APR-246. Together, our results indicate that, in at least a subset of AML cell lines and normal HSPCs, APR-246-induced ROS production and cytotoxicity are enhanced in the presence of WT p53 proteins."

Journal • P53WT • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Unbiased assessment of APR-246 responsive p53 mutants in ovarian cancer. (PubMed, Cell Death Discov) - "This study demonstrates that p53-specific effects of APR-246 are only observable in a narrow dosing window, under a specific set of conditions. Collectively, our results highlight the limitation of APR-246 as a p53-rescuing drug because of its overwhelming off-target effects on the redox system at doses that are sufficient to induce ferroptosis but insufficient to rescue mutant p53."

Journal • P53mut • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • TP53

Eprenetapopt in combination with Palbociclib exerts synthetic lethality in mantle cell lymphoma. (PubMed, Transl Oncol) - "These findings support a rational therapeutic strategy that exploits oxidative genomic instability and synthetic lethality via HR pathway disruption, offering a promising combination therapy for managing mut/delp53 MCL."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • BRCA1 • CCND1 • UHRF1

Eprenetapopt in combination with carboplatin in high-grade ovarian and triple negative breast cancer cell lines with acquired resistance to olaparib. (PubMed, Front Oncol) - "Combining eprenetapopt with carboplatin shows promising preclinical efficacy by enhancing cytotoxicity in olaparib-resistant models and demonstrating synergistic interaction; these data support the combination as a potential strategy to mitigate PARPi resistance and carboplatin cross-resistance in TP53 mutant HGSOC and TNBC cell lines. Although further studies are needed to elucidate the molecular mechanisms underlying the synergistic effect, here we point out the combination of eprenetapopt and carboplatin as a potential therapeutic strategy to address olaparib resistance in HGSOC and TNBC patients."

Journal • Preclinical • Breast Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • ANXA5 • BRCA1 • BRCA2

Inhibitory effects of induction of massive apoptosis (PRIMA-1MET) on tumorigenic chemokines in ovarian cancer cells (AACR 2026) - "PRIMA-1MET restores mutant p53 function and inhibits NF-κB-driven chemokine signaling, thereby restraining ovarian cancer progression and metastasis. These findings highlight its promise as targeted therapy."

Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • CCL20 • CXCL1 • CXCL8 • IL1B

Depletion of dominant-negative mutant p53 improves the efficacy of mutant p53 reactivators (AACR 2026) - "Reactivators include APR-246 (PRIMA1met) and arsenic trioxide (ATO). Moreover, our RT-PCR studies demonstrated that the combination of reactivator with depleters significantly increased mRNA expression of p53 downstream targets, as compared to that of the reactivator treatment alone. These results strongly suggest that the combination of reactivator drugs with depleter drugs could improve the treatment efficacy of reactivators to suppress mutp53-carrying tumors."

Clinical • Oncology • CDC37 • DNAJB1 • TP53

Anti-ROR2 therapies target cancer stem cells in triple-negative breast cancer (AACR 2026) - "We generated a high-affinity, humanized monoclonal antibody (mAb) specific for human ROR2 (h6E6) that could block ROR2 signaling, analogous to the capacity of our previous anti-ROR1 mAb (zilovertamab) to block ROR1 signaling. In NSG mice with ROR2+ TNBC PDX, intravenous h6E6, compared to control hIgG1, reduced expression of cancer stemness and EMT genes, as well as ERK1/2, NF-κB, and NRF2 pathway targets (FDR<0.0001), and caused a 5-fold reduction in NQO1, the main NRF2 downstream target, and increased sensitivity to APR-246 (p<0.001). By integrating rigorous experimental controls in both in vitro and in vivo studies using early-passage PDX, our work demonstrates that anti-ROR2 antibody therapy, combined with redox-modulating agents like APR-246, can effectively target CSC-driven disease persistence and therapy resistance in TNBC, supporting future clinical trials of h6E6 targeting ROR2+ TNBC."

Cancer stem • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ITK • NQO1 • ROR2

Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape. (PubMed, Eur J Pharmacol) - "Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • TP53

Functional genetics of APR-246 rescuable TP53 mutants (AACR 2024) - "Two of these mutants, C242F and G266V, are non-functional, damaging mutations which occur in patients. Identifying p53 mutants that can be rescued by APR-246 will help identify which patients may benefit most from treatment with the drug."

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

Synthetic lethal vulnerabilities stemming from inhibition of one carbon metabolism in anaplastic thyroid cancer (AACR 2024) - "We have identified and validated the main glycine transporter(s) in ATC cells and show that inhibition of 1C-Met is synthetic lethal with inhibition of glycine uptake.3- Impaired 1C-Met leads to increased oxidative stress and decrease of NADPH and glutathione levels. These alterations create a synthetic lethality relationship with the glutathione-depleting activity of PRIMA-1 (APR246), a small molecule originally identified as a compound restoring mutant p53 conformation and function, but later shown to be converted within cells into the reactive electrophile methylene quinuclidinone, which acts in a p53-independent manner through a variety of mechanisms, including reduction of cellular GSH levels.Our data shed light on the molecular consequences of 1C-Met upregulation in ATC and support the efficacy of novel rationally designed therapeutic approaches with curative intent not only for ATC, but also for other aggressive, dedifferentiated solid tumors."

Synthetic lethality • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • TP53

Genetic alterations and pharmacological response profiles from 10 cervical cancer cell lines (AACR 2024) - "All CLs were sensitive to Bortezomib, Omipalisib and Palbociclib. A large spectrum activity to Vorinostat, (HDAC inhibitor) in line with frequent (sensitizing) LoF alterations in epigenetic suppressor genes, contrasted with a selective response to other well-known CC drugs: Methotrexate, Gemcitabine, Sorafenib. Three out of CL were highly sensitive to APR246 (Eprenetapopt) as single agent. A string of LoF alterations (CSMD2/CSMD3, ZNF717, CDC27) had been previously associated with poor response to radiation or to chemo-radiation, in tumors and are present in most CLs which are derived from resistant tumors. Future objectives are to validate the present biomarker findings in the context of a clinical platform trial."

Preclinical • Cervical Cancer • Oncology • Solid Tumor • CDC27 • CSMD3 • OSBPL1A