EP31670

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.

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.

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.

P1, N=75, Recruiting, Epigenetix, Inc. | N=50 --> 75 | Trial completion date: Sep 2024 --> May 2025 | Trial primary completion date: Jun 2024 --> May 2025

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..

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.

Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer 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.

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.

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.

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.