eprenetapopt (APR-246) / Aprea - LARVOL DELTA

Profiling drug sensitivity in CLL B cells after BTK inhibitor progression using a novel drug panel (ASH 2025) - " Using the Mayo Clinic CLL Database and the Mayo Clinic CLL Tissue Bank, we identified 47 patients with RR CLL, all of whom experienced disease progressionon a BTKi (35 ibrutinib +/- CD20 antibody, 10 acalabrutinib +/- CD20 antibody, 2 other)...We also observed that RR CLL cohort exhibited significantly increased drug resistance to most of the tested drugs in the presence of BMSCs with corresponding increases in IC50s (with vs. without BMSCs, fold-change respectively): LP-118 3.92-fold, venetoclax 1.98-fold, carfilzomib 2.58-fold, TP-0903 1.65-fold, panobinostat 204.23-fold, TCIP1 1.91-fold, crenolanib 1.31-fold, idasanutlin 1.69-fold, belinostat 6.14-fold, LP-168 1.29-fold, eprenetapopt 3.44-fold and GTE 1.08-fold (11 out of 12 with p -values <0.05 except for GTE which was not significant, Mann-Whitney U test)... Our results highlight the spectrum of currently available drugs that show promise for therapeutic use in patients with RR CLL who experience disease..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • AXL • BCL2 • STAT6 • TP53

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

TP53 mutation promotes diffuse large B-cell lymphoma progression via mediating lactylation of ATP5E at Lys44 (ASH 2025) - "In contrast, knockdown of WT-TP53 promoted cell proliferation and shortened the G0/G1 phase, and significantly decreased LDHAexpression and intracellular lactate levels, whereas knockdown of WT-TP53 had no notable effect.Moreover, knockdown of MUT-TP53 reduced cellular sensitivity to APR-246, a small-molecule inhibitortargeting MUT-TP53...Functionalanalyses indicated that MUT-TP53 knockdown increased mtROS levels and decreased mitochondrialmembrane potential. Taken together, these findings suggest that DLBCL tissues and cells exhibitwidespread elevated lactylation modification levels mediated by TP53 mutation.In conclusion, our results revealed that TP53 mutations recruit and enhance ATP5E K44la, stabilizing itsexpression and modulating mitochondrial functions, thus providing a novel mechanism for metabolicreprogramming in DLBCL."

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

Synergistic enhancement of APR-246 anti-leukemic activity through ENO1 inhibition in TP53- and FLT3-mutated Acute Myeloid Leukemia (ASH 2025) - "HighENO1 expression correlated with shorter OS in TP53-mutant (HR 2.14, p = 0.008) and FLT3-ITD (HR 1.87, p= 0.013) cohorts.Functional loss-of-ENO1: shENO1 reduced clonogenicity by 48–64 % and increased APR-246 sensitivity(IC50 fold-reduction: MOLM-13 2.9, Kasumi-1 2.3; ZIP synergy 29–43).Ferroptosis signature: Combined ENO1 inhibition plus APR-246 elevated lipid-ROS 3.7-fold, decreasedGSH by 62 %, and triggered mitochondrial shrinkage/cristae loss—phenotypes reversed by ferrostatin-1.Molecular mechanism: RNA-seq revealed selective down-regulation of the glutathione/ferroptosis axis.ENO1 interacted with the E3-ligase NEDD4L; ENO1 loss augmented NEDD4L-mediated poly-ubiquitination and proteasomal degradation of SLC7A11 and GPX4, whereas MG132 restored GPX4levels.Genotype independence: Synergy was observed irrespective of TP53 or FLT3 status, indicating a p53-independent metabolic vulnerability.ConclusionsENO1 is an adverse prognostic biomarker in AML whose enzymatic or..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ENO1 • FLT3 • GPX4 • SLC7A11 • TP53

Multiomics-guided ex vivo drug sensitivity testing in Relapsed/Refractory Acute Myeloid Leukemia (ASH 2025) - "DNMT3A mutation suggested response tonavitoclax and KPT-330 (OR 8.4, p=0.18; OR 4.2, p=0.5, respectively). Associations were also foundbetween FLT3 mutation or short relapse latency among navitoclax responders (OR 4.2, p=0.5; eachrespectively).FLT3 mutants were associated with ponatinib sensitivity which was linked to FGFR3/FGFR4 upregulationin responders (OR 4.2, p=0.5). Furthermore, samples of patients who relapsed quickly were sensitive toeprenetapopt, wherein responders had upregulation of target gene MDM2 (OR 2.7, p=0.6). All patientsamples were highly sensitive to Panobinostat...Crucially, this proof-of-concept results supports a precision-medicine framework combininggenomic insights with functional drug screening, might offer actionable options for a patient group that isotherwise limited to supportive care alone. Further validation in larger cohorts of specific targets andtranslating and repurposing drugs post exvivo DS through potential clinical trials are ongoing."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2L1 • DNMT3A • FGFR3 • FGFR4 • FLT3 • IDH2 • MDM2 • MIR15A • MIR182

Durability of complete response outperforms complete response rates as a surrogate endpoint for advancing to phase III trials in high-risk myelodysplastic syndromes (ASH 2025) - "The HMA plus venetoclax cohort (n=59) had a CRrate of 11.9% (7/59) with 8.5% (5/59) durable CR, equating to 71% (5/7) of CRs durable. Clinical trial pts(n=41) receiving HMA plus novel agents (magrolimab, eprenetapopt, or tamibarotene) had a higher CRrate of 29.3% (12/41) with 24.4% (10/41) durable CR, translating into 83% (10/12) of CRs being durable.In subgroup analysis of pts with TP53-mutated MDS treated with HMA alone (n=242), achieving a durableCR was associated with a 38% reduction in risk of death (HR 0.62; 95% CI 0.39–0.97; p=0.037). Only durable CR translates into a survival benefit in HR-MDS. CR >6 months is a practical, clinicallymeaningful surrogate endpoint and may improve assessment of treatment efficacy and accelerate drugdevelopment in HR-MDS."

Clinical • P3 data • Hematological Malignancies • Myelodysplastic Syndrome • TP53

Dual-functional copper nanoplatform potentiates cuproptosis through p53 reactivation and metabolic reprogramming. (PubMed, J Colloid Interface Sci) - "Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu2+ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming...In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers."

Journal • Hematological Disorders • Oncology • DLAT • FDX1 • LIAS • TIGAR

Characterization and Preclinical Evaluation of AS-1763, an Oral, Potent and Selective Noncovalent BTK Inhibitor, in Chronic Lymphocytic Leukemia (ASH 2023) - P1 | "In primary CLL samples, AS-1763, pirtobrutinib or ibrutinib induced a modest apoptosis...Evaluation of drug interaction models utilizing Compusyn and Synergy Finder applications predominantly indicated additive effects between AS-1763 with BCL-2 inhibitor, venetoclax as well as p53 activator APR-246... AS-1763 is a selective ncBTKi that inhibits both wild-type and mutant BTKs listed in Table 1. In CLL cells, AS-1763 was effective in inhibiting BCR pathway signaling and sensitized cells to other agents such as venetoclax. Based on these encouraging data we have initiated a clinical trial to test AS-1763 in patients with CLL and other B cell malignancies who have failed or are intolerant to at least two prior lines of systemic therapy, including cBTKi (NCT05602363 Clinical Trials.gov)."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CCL3 • CD86 • MCL1

Post-transplant MRD Monitoring by TP53 Duplex Sequencing with APR-246 + Azacitidine Maintenance Predicts Outcomes. (PubMed, Blood Adv) - "Specifically, MRD negativity after cycle 12 strongly predicted OS (33.9 vs 20.4 months; P=.005) and EFS (33.9 vs 10.1 months; P=.004) with a trend for RFS (32.6 vs 13.5 months; P=.06). TP53 MRD was strongly predictive of outcomes, supporting incorporation of this assay in future novel strategies."

Biomarker • Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

APR-246 Overcomes Resistance to Asparaginase in Lymphoid Malignancies By Targeting Metabolic Cell Vulnerabilities (ASH 2024) - "KHYG-1 cells were treated with Erwinase associated with a ferroptosis inducer (RSL3) and/or a ferroptosis inhibitor (ferrostatin-1). In our work, APR-246/Erwinase combination effectively disrupts the balance between ROS generation and antioxidation dependent on glutamine/GSH metabolism in ASNase-R cells and leads to cell death by ferroptosis. Prospective phase I/II studies are now required to confirm the clinical efficacy of APR-246/Erwinase combination in ASNase-R ENKTL and ALL patients."

Acute Lymphocytic Leukemia • CNS Disorders • Extranodal Natural Killer/T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Oncology • Psychiatry • T Cell Non-Hodgkin Lymphoma • ANXA5 • TP53

APR246 Synergistically Enhances the Efficacy of Osimertinib against EGFR-P53 Co-Mutated Cells, Both Sensitive and Resistant (APSR 2025) - "Conclusion : In conclusion, the combination of APR246 with Osimertinib exerts synergistic effects against EGFR-P53 co-mutated sensitive and resistant cells. This strategy may delay the onset of resistance in TKI-sensitive patients with co-mutations clinically and partially reverse acquired resistance to Osimertinib."

Clinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • CDKN1A • EGFR • TP53

Mutant p53 Regulates Pyruvate Dehydrogenase Kinase 1 (PDK1) to Promote Proliferation and Migration in Breast Cancer. (PubMed, Cancer Sci) - "Moreover, PDK1 inhibition increased the therapeutic effect of APR-246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • EGR1 • PDK1 • TP53

Unraveling the Essential Role of Aberrant TET3 Expression in Acute Erythroid Leukemia, a Promising Epigenetic Target for Treatment (ASH 2024) - "We could detect a 32-41% increase in the drug sensitivity towards APR-246 upon KD of TET3 in the HEL cell line (n=3, p<0.01) indicating a potential benefit for combining drug treatment with TET3 targeting. Our results demonstrate an essential role of aberrant TET3 expression in AEL and identify TET3 as a promising epigenetic target for treatment in this challenging disease."

Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD34 • IL2 • IL6 • JAK2 • STAT5 • TET2 • TET3 • TNFA

Measurable Residual Disease Monitoring By Duplex Sequencing for TP53 in the Post Allogeneic Stem Cell Transplantation Study with Eprenetapopt (APR-246) + Azacitidine Strongly Predicts Outcomes (ASH 2024) - "Conclusions Many patients with TP53 mutant MDS/AML are MRD positive both before and after allo-HSCT, supporting the need for novel pre- and/or post-HSCT strategies to decrease relapse. Following completion of maintenance therapy with eprenetapopt and azacitidine, TP53 MRD was strongly predictive of outcomes, supporting incorporation of this assay in future novel strategies."

Biomarker • Residual disease • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Targeting p53 Improves Drug Resistance in Mantle Cell Lymphoma By Regulating Mitophagy-Dependent Ferroptosis (ASH 2024) - "MCL cell lines were treated with APR-246, an agent targeting mutant p53, and then cell proliferation, gene expression and ROS level were determined by CCK-8, qPCR and flow cytometry...However, these phenomena were not occurred in p53-deficient and p53-wild type cells. CUT&Tag assay revealed mechanistically that PINK1 was transcriptionally activated by p53.Conclusions : Our study elucidates the specific mechanism by which targeting mutant p53 could improve drug resistance in MCL by regulating mitophagy-dependent ferroptosis, and provides a new therapeutic strategy for chemotherapy resistant MCL patients."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • GPX4 • PINK1 • SLC7A11

LT1-3, a Slit2-Derived Peptide, Exhibits Anti-Tumor Activity and Improves Cisplatin Therapy. (PubMed, Cells) - "The p53 reactivator APR-246 restores sensitivity of p53R273H-expressing cells to LT1-3. Therefore, LT1-3 possesses multifunctional antitumor properties, directly inhibiting tumor cells and enhancing the efficacy of cisplatin, without causing toxicity to normal cells. Combining LT1-3 with cisplatin holds promise as a first-line therapy for lung cancer, while LT1-3 alone may be suitable for maintenance therapy."

Journal • Lung Cancer • Oncology • Solid Tumor • MAPK8 • PRKACA • SLIT2

The conundrum of drug development in higher-risk MDS: Lessons learned from recently failed phase 3 clinical trials. (PubMed, Blood) - "Aside from allogeneic transplantation, the current standard of care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazuridine...In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials."

Journal • P3 data • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Exploring Prima-1MET as a single agent or in combination with tamoxifen in breast cancer cells in vitro. (PubMed, Eur J Pharmacol) - "Furthermore, upon exposure to the combination of 10 μM Prima-1MET and 10 μM Tam, synergistic effects were detected, reflected by decreased viability, migration, altered morphology, and induction of apoptosis, along with downregulation of CCND1. Hence, these results emphasize the attractiveness of the combination of Prima-1MET and Tam as a therapeutic approach for TNBC and ER+ breast cancer, irrespective of p53 mutational status; therefore, these results encourage further preclinical and clinical studies, considering that the effective dose of Prima-1MET is less than the reported clinically achievable plasma level (∼80 μg/ml)."

Journal • Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCND1 • ER

Targeting the p53/xCT/GSH axis with PRIMA-1Met combined with Sulfasalazine shows therapeutic potential in Chronic Lymphocytic Leukemia (IWCLL 2025) - "Nowadays, new treatments are available for CLL patients carrying TP53 aberrations, such as ibrutinib and idelalisib, which inhibit the signalling pathway initiated by the B-cell antigen receptor, or venetoclax, which facilitates cell apoptosis. The same studies have also been performed in CLL primary cells carrying wild-type or mutated p53. Preliminary data and evidence will be presented and discussed."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • BIRC3 • NOTCH1 • SF3B1

Role of MRD Monitoring and Maintenance Therapy after HSCT in TP53 altered AML or MDS (ICBMT 2025) - "Overall, many favour a non-intensive approach irrespective of patient fitness with HMA +/- venetoclax outside of a clinical trial given dismal outcomes with intensive chemotherapy (with the potential exception of patients with a low VAF/single-hit mutation)...Notably, maintenance therapy with APR-246 (eprenetapopt) and azacitidine in a single arm study was favourable with a relapse free survival (RFS) of 12.5 months and an OS of 20.6 months from date of HCT...More importantly, patients that are durably MRD negative (e.g. at 1 year) have significantly improved OS and perhaps a TP53 MRD- endpoint would be the key in the above studies to support pivotal trials or perhaps even for registration purposes. Hopefully, incorporating novel TP53 MRD into optimization of outcomes to HCT for this subgroup can improve future outcomes."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • TP53

Novel p53 reactivators that are synergistic with olaparib for the treatment of gynecologic cancers with mutant p53. (PubMed, Transl Oncol) - "In this study, we investigated the effects of two purported p53 reactivators, HO-3867 and APR-246, on cell proliferation via half-maximal inhibitory concentration (IC50) analyses using CyQUANT DNA measurements, tumor growth in vivo and gene expression by bulk RNA sequencing in gynecologic cancer cell lines that harbor oncogenic mutations in p53. RNA sequencing data suggest that HO-3867 is acting through both p53-independent and p53-dependent pathways resulting in inhibition of DNA repair pathways including homologous recombination in p53 mutant cancer cells. Significance: The development of resistance to PARP inhibitors is a major problem and a cause of treatment failures in advanced gynecologic cancers, and we show that adding a p53 reactivator such as HO-3867 enhances the efficacy of PARP inhibitors in p53-mutant cancer models."

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

Setting a 3D model to study Chronic Lymphocytic Leukemia (IWCLL 2025) - "These preliminary results indicate that the gel seems to provide protection to CLL cells both in normal conditions and after treatment with PRIMA-1Met. This is probably related to the cell-scaffold interaction, which recreates a more physiological environment than 2D cultures. Based on these results, we will exploit this model to test new combinations of drugs already used in clinical practice to treat CLL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ANXA5 • BCL2 • PARP1

ROR1-Signaling Enhances Survival and Drug-Resistance of del(17p)/TP53-Mutated CLL by Mitigating Oxidative Stress Via Activation of NRF2 (IWCLL 2025) - "This pathway underpins the association between ROR1Hi expression, CK, and poor outcomes, while zilovertamab emerges as a strategy to counteract these mechanisms. Combining ROR1 inhibition with BTKis or ROS-inducing therapies (e.g., APR-246) could mitigate resistance in high-risk CLL, offering a dual-pronged approach to target both survival signaling and genomic instability."

Oxidative stress • Chronic Lymphocytic Leukemia • Hematological Malignancies • CCNA1 • NQO1 • ROR1 • SQSTM1 • TP53 • WNT5A

Progress in Higher-Risk Myelodysplastic Syndromes (SOHO 2025) - P3 | "15 Nonetheless, the current treatment landscape for HR-MDS is limited to HMA monotherapy, either parenteral (azacitidine or decitabine) or a more recently available oral option (decitabine/cedazuridine), followed by allogeneic hematopoietic stem cell transplant when feasible, based on patient fitness and donor availability...Eprenetapopt 18,19 (P53-refolding agent), pevonedistat 20 (NEDD8 inhibitor), sabatolimab, 21 magrolimab 22 (anti-CD47 monoclonal antibody promoting macrophage-induced phagocytosis), and most recently, tamibarotene (a retinoid) (DeZern et al accepted Blood Advances 2025) were all once drugs many hematologists hoped could alter the course of disease beyond the current limited armamentarium available in HR-MDS...Conclusions Given an increased understanding of disease biology, improved efforts at predicting outcomes based on baseline genetic alterations, the development of more pragmatic response criteria, and the investigation of novel..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53

The Multifaceted Role of p53 in Cancer Molecular Biology: Insights for Precision Diagnosis and Therapeutic Breakthroughs. (PubMed, Biomolecules) - "Small molecules restoring wild-type p53 activity or disrupting mutant p53 interactions, such as APR-246 and MDM2 inhibitors, show promise in clinical trials...In conclusion, deciphering p53's complex biology underscores its unparalleled potential as a biomarker and therapeutic target. Integrating multi-omics analyses, functional genomic screens, and real-world clinical data will accelerate the translation of p53-focused research into precision oncology breakthroughs, ultimately improving patient outcomes."

IO biomarker • Journal • Review • Oncology