EP31670 / Epigenetix - LARVOL DELTA

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

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

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

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

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

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

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

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

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

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

Androgen receptor variants confer castration resistance in prostate cancer by counteracting antiandrogen-induced ferroptosis. (PubMed, Cancer Res) - "Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in PCa cells...However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anti-cancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to PCa progression."

Journal • Genito-urinary Cancer • Metabolic Disorders • Oncology • Prostate Cancer • Solid Tumor • SLC7A11

Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Epigenetix, Inc. | Not yet recruiting ➔ Recruiting | Initiation date: Sep 2022 ➔ Dec 2022

Enrollment open • Metastases • Trial initiation date • Genito-urinary Cancer • NUT Midline Carcinoma • Oncology • Prostate Cancer • Solid Tumor

GelMA, Click-Chemistry Gelatin and Bioprinted Polyethylene Glycol-Based Hydrogels as 3D Ex Vivo Drug Testing Platforms for Patient-Derived Breast Cancer Organoids. (PubMed, Pharmaceutics) - "BCa organoids responded to doxorubicin, EP31670 and paclitaxel treatments with increased IC concentrations on organoids compared to 2D cultures, and highest IC for organoids in GelSH. Cell viability after doxorubicin treatment (1 µM) remained >2-fold higher in the 3D gels compared to 2D and doxorubicin/paclitaxel (both 5 µM) were ~2.75-3-fold less potent in GelSH compared to PEG hydrogels. The data demonstrate the potential of hydrogel matrices as easy-to-use and effective preclinical tools for therapy assessment in patient-derived breast cancer organoids."

Journal • Preclinical • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2

Dual inhibition of BET and HAT/p300 suppresses colorectal cancer via DR5- and p53/PUMA-mediated cell death. (PubMed, Front Oncol) - "Our study demonstrates NEO2734 potently suppresses CRC cells in vitro and in vivo by simultaneously upregulating PUMA and DR5 to induce cell death. Further studies of NEO2734 for treating CRC are warranted."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MYC

Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=50 | Not yet recruiting | Sponsor: Epigenetix, Inc.

New P1 trial • Genito-urinary Cancer • NUT Midline Carcinoma • Oncology • Prostate Cancer • Solid Tumor

Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer. (PubMed, Oncogene) - "Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC."

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

Anti-tumor activity of a dual BET/CBP/EP300 inhibitor, NEO2734, in undifferentiated pleomorphic sarcomas and identification of genes involved in resistance (AACR 2022) - "Doxorubicin represents the standard 1st line of treatment for patient with advanced disease...We previously found that at least a subgroup of UPS is characterized by a strong expression of MYC-targets pathway (Toulmonde et al, EBIOMEDICINE, 2020) The anti-tumor activity of three compounds which inhibits either CBP/P300 only (CPI-637) or dual inhibitors of both BET and CBP/P300 proteins (NEO1132 and NEO2437) was investigated in four UPS cell lines and two patient-derived xenografts (PDX) established at Institut Bergonié (Bordeaux, France)... Dual inhibition of BET and CBP/P300 proteins has promising antitumor activity in undifferentiated pleomorphic sarcoma. Suppressing hnRNPU may enhance the activity of dual BET and P300/CBP bromodomain inhibitor in sarcoma and other cancers."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • AURKA • CCNB1 • EP300 • MYC • PLK1