EP31670 / Epigenetix - LARVOL DELTA

Identifying novel ’druggable’ targets via Npm1A-turboid fusion and mass spectrometry to overcome genetic or adaptive resistance to menin inhibitors in mtNPM1 AML (ASH 2025) - "Treatment with revumenib may also cause emergenceof hot spot mutations in menin (e.g., S160T, M327V, M327I, G331D, G331R, and T349M) exhibitingreduced affinity to MI-binding...OCI-AML3 MEN1-M327I cells were resistant toSNDX-50469, ziftomenib, and DS1594b, but sensitive to the second-generation MI, bleximenib, aspreviously reported.To identify novel 'druggable' targets in mtNpm1 AML cells either sensitive or resistant to MI, we knockedin TurboID by CRISPR/Cas9 into the C-terminus of the mtNpm1 gene in OCI-AML3 cells...When combined with a BET inhibitor (pelabresib) ora novel dual BET/HAT inhibitor (NEO2734/EP31670), both RocA and talazoparib induced synergisticlethality in the sensitive OCI-AML3 and OCI-AML2-Npm1A KI, as well as the MI-resistant (OCI-AML3-Menin-M327I or the OCI-AML3 MITR) cells...Exvivo treatment with EP31670 and RocA or talazoparib induced synergistic loss of viability in MI (SNDX-50469)-resistant, patient-derived (N = 3) mtNpm1 AML cells. In the..."

IO biomarker • Acute Myelogenous Leukemia • AURKA • CDK9 • CDKN1A • EIF4A1 • EIF4A2 • FLT3 • HOXA9 • IL7R • IRAK4 • KMT2A • MEIS1 • MEN1 • MYC • NPM1 • PLK1 • S100A8 • SF3B1 • SMARCA2 • TP53

OVERCOMING GENETIC OR ADAPTIVE RESISTANCE TO MENIN INHIBITORS IN MUTANT NPM1 AML WITH NOVEL ’DRUGGABLE’ TARGETS IDENTIFIED VIA NPM1A-TURBOID FUSION AND MASS SPECTROMETRY (EHA 2026) - "Rocaglamide A (RocA), an eIF4A inhibitor, and talazoparib (TLZ), a PARP inhibitor, induced greater loss of viability in OCI-AML2-mtNPM1 cells relative to parental cells...When combined with a dual BET/HAT inhibitor (NEO2734/EP31670 - EP), both RocA and TLZ induced synergistic lethality in sensitive OCI-AML2-NPM1A KI and OCI-AML3, as well as MI-resistant (OCI-AML3-Menin-M327I or -MI-tolerant/resistant) cells...Summary/Conclusion Collectively, these findings highlight the preclinical efficacy of eIF4A and PARP inhibitors and strongly support the rationale to further evaluate the efficacy of combinations involving these agents against mtNPM1 Menin inhibitor sensitive and resistant AML. Model for Identifying Putative mtNpm1 Protein Interactors by CRISPR Knock-In (KI) of TurboID into the Npm1A Gene in OCI-AML3 Cells."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • AURKA • BAK1 • CDK9 • CDKN1A • EIF4A1 • EIF4A2 • FLT3 • HOXA9 • IRAK4 • IRF8 • KMT2A • MEIS1 • MYC • NPM1 • PLK1 • SF3B1 • SMARCA2

DUAL BET/HAT INHIBITOR–BASED COMBINATIONS EXERT SYNERGISTIC LETHALITY AGAINST MYELOPROLIFERATIVE NEOPLASMS (MPN) TRANSFORMED TO AML (EHA 2026) - "Additionally, treatment with BETi (e.g., birabresib) reduced leukemia burden and induced clinical remissions...Results In present studies, we elucidated the gene-expression alterations and lethal activity of dual BET/HAT inhibitor EP31670 alone and in combination with other targeted agents to achieve superior preclinical efficacy in post-MPN sAML cells that are sensitive or resistant to JAKi or BETi...Notably, co-treatment with EP and ruxolitinib induced synergistic lethality in cultured and patient-derived (PD) post-MPN sAML...We also determined that co-treatment with EP and CDK7i SY-5609 (SY) was synergistically lethal in sAML cell lines including those resistant to JAKi or BETi, as well as PD MPN-sAML cells...Co-treatment with EP and SY resulted in significantly greater reduction in leukemia burden and further improved the overall survival of the mice than treatment with each agent alone (p < 0.05). Summary/Conclusion These findings demonstrate promising..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • BCL2 • BRD4 • CALR • CDK6 • CDKN1A • EP300 • HEXIM1 • JAK2 • MYC • PIM1

ASXL1 mutations in AML are associated with a distinct epigenetic state that results in vulnerabilities to epigenetic-targeted agents (AACR 2025) - "Notably, compared to parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to standard anti-AML, chemotherapeutic agents, including cytarabine, etoposide and daunorubicin. Our findings confirm the previously published discovery that the presence of mtASXL1 confers an increased sensitivity to BETi inhibitors, e.g., pelabresib or birabresib...Importantly, in the NSG mice engrafted with OCIAML3 ASXL1 Y591*, monotherapy with NEO2734, pelabresib or SEL120 significantly reduced AML burden. Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or mediator-kinase inhibitor."

Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • ASXL1 • AURKA • BAP1 • CDK9 • E2F1 • EP300 • FZD5 • HOXA9 • MEIS1 • MYC • PLK1 • SPI1 • TCF7L2

ASXL1 Mutations in AML Are Associated with a Distinct Epigenetic State Which Highlights Vulnerabilities to Specific Epigenetic-Targeted Agents (ASH 2024) - "Notably, compared to parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to standard anti-AML chemotherapeutic agents, including cytarabine, etoposide and daunorubicin...Our findings also demonstrate and confirm that mtASXL1-expressing AML cells exhibited increased sensitivity to BETi (pelabresib or birabresib)...Importantly, in the NSG mice engrafted with luciferized OCIAML3 ASXL1 Y591*, monotherapy with NEO2734 (5 mg/kg QD), pelabresib (30 mg/kg QD) or SEL120-34A (40 mg/kg QD), compared to vehicle control, significantly reduced AML burden. Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or inhibitor of mediator kinase."

Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Oncology • Targeted Protein Degradation • ASXL1 • AURKA • BAP1 • BRD4 • CD14 • CDK9 • E2F1 • FZD5 • HOXA9 • MEIS1 • MYC • NDUFA2 • PLK1 • SPI1 • TCF7L2

ASXL1 Mutations in AML Are Associated With a Distinct Epigenetic State That Results in Vulnerabilities to Epigenetic-Targeted Agents (SOHO 2025) - " Notably, compared with parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to chemotherapeutic agents, including cytarabine, etoposide, and daunorubicin. In contrast, mtASXL1-expressing AML cells exhibited increased sensitivity to bromodomain and extraterminal inhibitors (BETi; pelabresib or birabresib)... These findings highlight that rationally targeted agents including NEO2734, pelabresib, and SEL120 or their combinations can potentially exert significant anti-AML efficacy against AML cells with mtASXL1."

Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • ASXL1 • BAP1 • BCL9L • DVL1 • HOXA9 • MEIS1 • MYC • SPI1 • TCF7L2 • WNT5B • WNT7B

Preclinical efficacy of dual BET/HAT inhibitor–based combinations against post myeloproliferative neoplasm secondary AML cells (ASH 2025) - "Notably, treatment with BETi (e.g., OTX015) wasshown to reduce leukemia burden and improve survival in xenograft models of post-MPN sAML cells.However, BETi resistance and BETi-refractory disease develop uniformly...Compared to pan-BET inhibitor INCB057643,treatment with EP31670 induced significantly greater in vitro lethality in HEL92.1.7 and SET2 cells.Notably, in vitro treatment of cell lines and PD post-MPN sAML cells with EP31670 in combination withruxolitinib, for 72 to 96 hours induced synergistic lethality, as determined by SynergyFinder...Notably, co-treatment with EP31670 and SY-5609resulted in significantly greater reduction in leukemia burden and overall survival of the mice thantreatment with each agent alone (p < 0.05). These findings demonstrate promising preclinical activity ofEP31670 against cellular models of MPN-sAML and strongly support the rationale to further evaluate thein vivo efficacy of EP31670-based combinations against advanced MPN with..."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • ASXL1 • BCL2 • BRD4 • CALR • CDK6 • CDKN1A • DNMT3A • EP300 • HEXIM1 • IL6 • JAK2 • MYC • PIM1 • RUNX1 • STAT5 • STAT5AWqe • TP53

Pharmacologic inhibition of RBBP4/p300-mediated homologous recombination activity enhances glioblastoma sensitivity to temozolomide. (PubMed, Neurooncol Adv) - "Upstream regulators of the homologous recombination (HR) repair pathway are promising targets for overcoming temozolomide (TMZ) resistance. Both compounds inhibited H3K27Ac and were detectable in orthotopic tumors by LC-MS/MS and significantly extended survival alone and in combination with TMZ. These findings suggest that the RBBP4/p300-axis is a key regulator of HR-mediated repair of TMZ-induced DSBs, and inhibition by either CCS1477 or NEO2734 may be beneficial as monotherapy, but further studies are needed to determine the benefit of combining these agents with TMZ."

Journal • Brain Cancer • Eye Cancer • Glioblastoma • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • BARD1 • BRCA1 • BRIP1 • EP300 • FIGNL1 • RAD50 • RAD51 • RBBP4

Discovery of CZL-149: A Novel, Highly Potent, and Orally Bioavailable Dual Inhibitor Targeting BET and p300/CBP Bromodomains with Strong Antitumor Efficacy. (PubMed, J Med Chem) - "CZL-149 displays favorable drug-like properties and metabolic profile, achieving 107% oral bioavailability in mice. Importantly, CZL-149 outperformed NEO2734 in both antitumor efficacy (TGI = 78%) and safety in vivo, highlighting its potential as an advanced preclinical candidate worthy of further development."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • CREBBP

Preclinical development and characterization of IACS-16559, a dual bromodomain inhibitor of CBP/EP300, and its potential in AML subtypes (AACR 2025) - "Clinical validation of bromodomain inhibition of paralogs CBP and EP300 is undergoing in multiple clinical trials, including both hematological diseases and solid tumors, using EP31670, CCS1477 and TT125-802, while selective CBP or EP300 inhibition is being explored preclinically. However, in contrast, long-term treatment in the MLL-AF9 (MOLM14) model resulted in antagonistic effects. These findings underscore the complexities of combinatorial therapeutic development and emphasize the critical need for careful selection of robust therapeutic combinations and consideration of the genetic background in the target disease."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BRD4 • EP300

Enhanced Antitumor Activity and Induction of Immunogenic Cell Death in NUT Carcinoma Cells by Combining Oncolytic Viruses with the Dual Inhibitor NEO2734. (PubMed, Viruses) - "To investigate multimodal therapeutic approaches that combine epigenetic modulation with immunogenic and cytotoxic effects of oncolytic viruses (OVs), we evaluated two recombinant OVs, including the herpes simplex virus talimogene laherparepvec (T-VEC) and a measles vaccine virus (MeV-GFP), in combination with NEO2734 in four distinct NC cell lines. Evaluation of immunogenic cell death (ICD) markers displayed elevated ATP and HMGB1 levels and increased surface calreticulin with T-VEC and NEO2734 combinations. Overall, these findings indicate that combining OVs with BET/p300 inhibitors elicits potent antitumor responses, supports synergistic interactions and immunogenicity, and warrants further investigation in multimodal therapeutic strategies for NC."

IO biomarker • Journal • Herpes Simplex • Infectious Disease • Measles • NUT Midline Carcinoma • Oncology • BRD4 • CALR • HMGB1 • NUTM1

Discovery of ZX079 as a Dual PROTAC Degrader Targeting BRD4/CBP in Acute Myeloid Leukemia. (PubMed, J Med Chem) - "The lead compound, 10k (ZX079), induces potent, dose- and time-dependent degradation of BRD4 and CBP and demonstrates superior suppression of oncogenic transcription and inhibition of AML cell proliferation compared with the dual BET/CBP inhibitor NEO2734. In vivo, 10k significantly reduces tumor growth in an AML xenograft model with TGI over 90%. Collectively, these findings highlight dual degradation of BRD4 and CBP as a promising strategy for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • BRD4

Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer. (PubMed, J Med Chem) - "Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BRD4 • MYC

EP31670, a dual-BET + p300 inhibitor, demonstrates pre-clinical efficacy, including in combination with JAK inhibition, in the hMPLW515L adoptive transfer model of myelofibrosis (MF) (ASH 2025) - P1 | "Approximately 3 weeks post-transplant, mice werebled and cohorted into respective vehicle (VEH), EP31670 (3.5mg/kg BID), ruxolitinib (RUX; 60mg/kg BID),or combination (Combo) therapy arms. In line with early results from ongoing human clinical trials, a low dose of EP31670demonstrates significant pre-clinical efficacy in MF models—with reduction of pro-inflammatorycytokines, spleen volume, hematologic parameters, and BM fibrosis—both alone and in combinationwith JAKi. Notably, the efficacious dose of EP31670 in these mouse studies, in combination with JAKi, waslower than what is usually required for EP31670 efficacy when applied as monotherapy in other mousetumor models. Dual BET+p300 inhibition suppresses pro-inflammatory cytokine production in vivo andrepresents a potential alternative to other emerging epigenetic modifying therapies for MF treatment."

Combination therapy • Preclinical • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • BRD4 • EP300 • IL13

Clone-specific epigenetic regulatory mechanisms in ASXL1-mutant chronic myelomonocytic leukemia (ASH 2025) - P1 | "ASXL1mt CMML is characterized by the up-regulation of several leukemogenic driver genesincluding HOXA9 and its co-factor MEIS1, secondary to the activation of genotype-specific enhancers. Thepreferential accessibility of these enhancers can be defined between ASXL1mt and ASXL1wt cells withinpatients. The enhancers of interest interact with p300 and BRD4 in myeloid cell lines and targeting themwith the novel dual p300/BRD4 inhibitor, EP31670, induces therapeutic responses at low nanomolar drugconcentrations in vitro, preferentially in ASXL1-mutant cells."

Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • ASXL1 • BRD4 • HOXA9 • MEIS1 • TET2

Targeting Oncogenic Enhancers in ASXL1-Mutant Chronic Myelomonocytic Leukemia (ASH 2023) - "In CMML patients, truncating ASXL1 mutations are associated with the activation of genotype-specific enhancers and the recruitment of an extended repertoire of transcriptional regulators including BRD4, CBP, and p300. In a model system, the disruption of an enhancer predicted to govern the expression of the leukemogenic driver HOXA9, led to a significant down-regulation of HOXA9 expression. Pharmacologically disrupting the oncogenic interaction at such enhancers with EP31670 in primary patient samples led to significant therapeutic effects at nanomolar drug concentrations in a genotype-specific manner."

Chronic Myelomonocytic Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • Oncology • ASXL1 • BRD4 • HOXA9 • KEAP1 • MEIS1

Targeting Aberrant DLK1 Re-Expression in ASXL1-Mutant Chronic Myelomonocytic Leukemia with BRD4 / p300-Directed Epigenetic Small Molecule Therapy (ASH 2024) - P1 | "The distal enhancer EH38D2760182 was found to bind BRD4 and p300 and the pharmacologic disruption of BRD4 / p300 activity in model systems led to the downregulation of DLK1. The clinical-grade dual inhibitor of BRD and CBP / p300 EP31670 is currently being investigated in patients with ASXL1-mutant chronic myeloid neoplasms (NCT05488548)."

Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ASXL1 • BRD4 • DLK1 • SRSF2 • TET2

The important role of the histone acetyltransferases p300/CBP in cancer and the promising anticancer effects of p300/CBP inhibitors. (PubMed, Cell Biol Toxicol) - "Importantly, two p300/CBP bromodomain inhibitors, CCS1477 and FT-7051, as well as the dual p300/CBP and BRD4 bromodomain inhibitor NEO2734 have entered Phase I and IIa clinical trials in patients with advanced and refractory hematological malignancies or solid tumors. Taken together, the identification of p300/CBP as critical drivers of tumorigenesis and the development of p300/CBP inhibitors and proteolysis-targeted-chimaera protein degraders represent promising avenues for clinical translation of novel cancer therapeutics."

Journal • Review • Developmental Disorders • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • Targeted Protein Degradation • BRD4 • CREBBP

Dual inhibition of BET and EP300 has antitumor activity in undifferentiated pleomorphic sarcomas and synergizes with ferroptosis induction. (PubMed, Transl Oncol) - "Among the three compounds tested, the dual inhibitor NEO2734 was the most potent, decreased the viability of UPS cells in vitro through a regulation of E2F targets and cell cycle and decreased the tumor growth in vivo. Moreover, we identified GPX4 as a gene involved in resistance and showed synergy between BET inhibition and ferroptosis induction. The present study demonstrated that dual BET/EP300 inhibitors have a relevant antitumor activity in a subgroup of UPS characterized by expression of MYC-targets pathway and identified a potent combination therapeutic strategy that deserves further investigation in the clinical setting."

Journal • Oncology • Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • EP300 • GPX4 • MYC

Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov) - P1 | N=75 | Recruiting | Sponsor: Epigenetix, Inc. | N=50 ➔ 75 | Trial completion date: Sep 2024 ➔ May 2025 | Trial primary completion date: Jun 2024 ➔ May 2025

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Chronic Myelomonocytic Leukemia • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • NUT Midline Carcinoma • Oncology • Prostate Cancer • Solid Tumor

Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer (EACR 2024) - "NEO2734 reduced the growth of both AR-positive and AR-null organoids, as measured by multiple independent readouts of viability, size and composition, and caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced ASCL1 levels and other neuroendocrine markers, and reduced tumour growth in vivoConclusion These results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the cliic."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • AR • ASCL1 • BRD4

Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer. (PubMed, J Pathol) - "A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition.."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • AR • ASCL1 • BRD4

Characteristics of anticancer activity of CBP/p300 inhibitors - Features of their classes, intracellular targets and future perspectives of their application in cancer treatment. (PubMed, Pharmacol Ther) - "The promising anticancer efficacy in in vitro and mice models led CCS1477 and NEO2734 to clinical trials. However, none of the described inhibitors is perfectly specific to CBP/p300 since they share similarity of a key functional domains with other enzymes, which are critically associated with cancer progression and their antagonists demonstrate remarkable clinical efficacy in cancer therapy. Therefore, we revise the possible and clinically relevant off-targets of CBP/p300 inhibitors that can be blocked simultaneously with CBP/p300 thereby improving the anticancer potential of CBP/p300 inhibitors and pharmacokinetic predicting data such as absorption, distribution, metabolism, excretion (ADME) and toxicity."

Journal • Review • Oncology

The interaction of radiotherapy and dual inhibition of BET and HAT/p300 in colorectal cancer. (ASCO-GI 2024) - "EP31670 enhanced RT-induced growth arrest, reduced proliferation, and enhanced cell death in HCT116 CRC cells in synergy with the RT. Additional preclinical studies, in vivo studies, and eventual clinical studies can be conducted to further exploit this synergistic interaction."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ANXA5

Automation, live-cell imaging, and endpoint cell viability for prostate cancer drug screens. (PubMed, PLoS One) - "We demonstrated effectiveness and reliability of this pipeline through validation of the established finding that the first-in-class BET and CBP/p300 dual inhibitor EP-31670 is an effective compound in reducing ADPC and CRPC cell growth. In addition, we found that insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib is a potential pharmacological agent against highly lethal and drug-resistant NEPC NCI-H660 cells. This protocol can be employed across other cancer types and represents an adaptable strategy to optimize assay-specific cell growth conditions and simultaneously assess drug efficacy across multiple cell lines."

Journal • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • AR