NEO1132 / Epigenetix, adMare BioInnovations - LARVOL DELTA

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

The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells. (PubMed, Hemasphere) - "Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation."

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

[VIRTUAL] THE NOVEL ORAL BET-CBP/P300 DUAL INHIBITOR NEO2734 IS HIGHLY EFFECTIVE IN ERADICATING ACUTE MYELOID LEUKEMIA BLASTS AND STEM/PROGENITOR CELLS (EHA 2021) - "Oral treatment with NEO2734 or NEO1132 did not significantly reduce the weight of the mice, and did not affect the survival of normal mouse hematopoietic cells. Conclusion The dual BET-CBP/P300 inhibitor NEO2734 eliminates AML blasts and LSCs/progenitors in a nanomolar concentration, implicating that dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • MYC

Targeting both BET and CBP/EP300 proteins with the novel dual inhibitors NEO2734 and NEO1132 leads to anti-tumor activity in Multiple Myeloma. (PubMed, Eur J Haematol) - "The dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM."

Journal • Gene Therapies • Hematological Malignancies • Multiple Myeloma • Oncology • EP300 • IRF4 • MYC

Novel dual BET/p300 bromodomain inhibitors therapeutically inhibit BRD4-NUT driven NUT Carcinomas (AACR-NCI-EORTC 2019) - "Next, we investigated whether inhibiting both BRD4 and p300, by blocking the BDs of BRD4 and p300 with a novel dual inhibitor class of compounds, termed ‘NEO’ (NEO2734 and NEO1132), might exhibit greater inhibition of NC growth than BET BD inhibition alone...Most strikingly, the lead clinical NEO compound completely abrogated NC tumor growth in our pilot disseminated xenograft mouse study, which greatly prolonged survival as compared to a lead clinical BET inhibitor (GSK762) or “standard” chemotherapy (cisplatin/etoposide) commonly used for NC. These data support our hypothesis that p300 recruitment is necessary for the oncogenic functions of BRD4-NUT and dual targeting of BET and p300 BDs represents a promising therapeutic option for NC patients. Future studies are necessary to determine the relative contribution of BET versus p300 BD inhibition to preventing NC growth by NEO compounds."

NEO2734, a novel dual BET and P300/CBP bromodomain inhibitor, is more active in NUT midline carcinoma than single agent BET or P300/CBP inhibitors (AACR-NCI-EORTC 2019) - "As BET inhibitors have shown activity in NMC and P300 is important in its pathophysiology, we examined the pre-clinical activity of NEO2734 and NEO1132, novel dual BET and P300/CBP inhibitors (Giles et al Abs #2510 ESMO 2018), in NMC. ResultConsidering the important roles of BET proteins and P300 in NMC, two NMC-cell lines (1015 and 14169, C. French: Brigham and Women’s Hospital) were treated with dual BET and P300/CBP inhibitors NEO2734 and NEO1131 (Epigene Therapeutics Inc), BET inhibitors JQ1 and iBET155 (GSK525762) (Sigma-Aldrich) and P300/CBP inhibitor CPI-637 (MedChem Express) for comparison...We also observed the presence of two different cell populations (adherent and suspension cells) in both NMC cell lines with adherent cells being more resistant to NEO2734, Differences in the responses to NEO2734 in NMC are being studied to molecularly identify biomarkers of resistance. These data support the inclusion of patients with NMC in clinical studies of NEO2734."