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

P1/2, N=350, Recruiting, CellCentric Ltd. | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P1, N=130, Recruiting, Opna Bio LLC | Not yet recruiting --> Recruiting

The binding free energy of EP300 with 4449-0460 was -10.93 kcal/mol, and mainly came from the nonpolar energy term (ΔGnonpolar). Pro1074, Phe1075, Val1079, Leu1084, and Val1138 were the key residues in EP300/4449-0460 binding with more -1 kcal/mol energy contribution. 4449-0460 was a promising inhibitor targeting EP300, which had implications for the development of drugs for EP300-related diseases.

P1, N=130, Not yet recruiting, Opna Bio LLC

P1, N=50, Recruiting, TOLREMO therapeutics AG

Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types...Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477...14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.

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..

Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182...Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.

P1, N=50, Recruiting, Aurigene Discovery Technologies Limited | Not yet recruiting --> Recruiting

Together these data support the further development of inobrodib for the treatment of peripheral T cell lymphoma. Expansion continues with a focus on T-cell lymphomas, which may be driven by IRF4 and GATA3.

In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.

I-CBP112 significantly reduced ABCB1, ABCC1, ABCC2, ABCC3, ABCC5 and ABCG2 in all resistant lines, as well as ABCC10 in TNBC and ABCC4 in paclitaxel-resistant NSCLC, thereby increasing intracellular drug accumulation and cytotoxicity in 2D and 3D cultures...In silico assay of ADMET properties confirmed the desired pharmacokinetic features of I-CBP112. The results suggest that the CBP/p300 inhibitor is a promising co-adjuvant to chemotherapy in drug-resistant cancer phenotypes, capable of decreasing ABC transporter expression.

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.

P1/2, N=250, Recruiting, CellCentric Ltd. | Trial completion date: Mar 2024 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Jun 2025

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.

Here, we show that IMiDs synergize with EP300 inhibitors (EP300i) but that transcriptional heterogeneity can overcome IKZF1, IKZF3, and EP300 dependency to maintain MYC and IRF4 expression and mediate IMiD resistance. Human myeloma cell lines (HMCL) were treated with pomalidomide (POM) and EP300i (GNE781 and CCS1477) and proliferation was measured by cell count...shRNA knockdown and doxycycline-inducible lentiviral overexpression were used for functional characterization of BATF proteins... These data indicate that MYC and IRF4 downregulation are critical events for IMiD responses, which can be augmented through combined EP300i. The overlap of P300 and IKZF1 binding sites provides a molecular explanation for the observed synergy between POM and EP300i. These data provide a strong preclinical rationale for the ongoing clinical trial of POM+CCS1477 (NCT04068597).

RNAseq was used to assess the transcriptional effects of CCS1477, and ChIPseq was used to identify drug-induced changes in EP300/CBP chromatin binding, H3K27 acetylation, and chromatin accessibility. In preclinical analyses CCS1477 induces potent growth inhibition through inducing cell cycle arrest at low nanomolar concentrations (GI50 < 100nM) in myeloma cell lines, including lenalidomide refractory lines. CCS1477 treatment rapidly alters EP300/CBP chromatin occupancy and subsequent gene expression programs, resulting in potent anti-tumour activity in multiple myeloma cells. These encouraging data provide a strong rationale for the ongoing phase I/IIa clinical trial investigating the safety and efficacy of CCS1477 in advanced haematological malignancies (NCT04068597), and provide mechanistic insight into the activity of CCS1477 against multiple myeloma.

P1, N=50, Not yet recruiting, Aurigene Discovery Technologies Limited

Inobrodib is well tolerated and demonstrates promising efficacy in heavily pre-treated patients with RRMM. These results support the continued development of inobrodib in combination with standard therapies in patients with RRMM.

However, the CBP/p300 inhibitor CCS-1477 abolished this phenomenon, suggesting that CBP/p300-mediated acetylation of KPNA2 promoted KPNA2 nuclear export in lung cancer cells. Collectively, our findings suggest that the CBP/p300 positively regulates KPNA2 acetylation, which enhances its cytosolic localization and suppresses its oncogenic activity in lung cancer.

Our findings demonstrate FT-6876 as a promising new CBP/p300 bromodomain inhibitor, with efficacy in preclinical models of AR+ breast cancer.

CCS1477 (inobrodib) is a first-in-class bromodomain inhibitor developed by Cell Centric and targeted to inhibit CBP/p300 mediated bromodomain activity, and thus regulate cell survival...In conclusion, these studies identify CBP/p300 as a driver of PCa tumorigenesis through coordinated control of critical transcriptional events and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed therapies. Combined, these studies have the capacity for significant near-term impact in the prevention and/or management of metastatic disease.

Moreover, the EP300 inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML.

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.

Finally, we evaluated the activity of CCS1477 in an OPM-2 xenograft model in combination with existing standard of care agents in myeloma and observed additive or synergistic growth inhibitory activity with each of bortezomib, lenalidomide and vorinostat in combination with CCS1477. These encouraging data suggest strong promise for the clinical utility of CCS1477 in the treatment of multiple myeloma as monotherapy and/or in combination with standard of care agents.

Accumulated studies have revealed that some key factors associated with the mechanism of IMiD resistance to MM cells. Some agents represent promising new therapeutics of MM to regulate the IRF4/MYC axis by inhibiting BRD4 expression or signaling pathway activation.

P1/2, N=350, Recruiting, CellCentric Ltd. | N=200 --> 350 | Trial completion date: Jun 2022 --> Mar 2024 | Trial primary completion date: Jun 2022 --> Mar 2024

These observations illuminate a clinically relevant hypothesis for combining CCS1477 with immune checkpoint blockade in the treatment of cancer.

XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30...We, therefore, combined XP-524 with an anti-PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.

P1/2, N=200, Recruiting, CellCentric Ltd. | Trial completion date: Dec 2021 --> Jun 2022 | Trial primary completion date: Dec 2021 --> Jun 2022