inobrodib (CCS1477)

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.

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.

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.

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

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.

We then determine the extent that two DNA repair inhibitors (CCS1477, a small molecule inhibitor of p300, and ART558, a small molecule inhibitor of polymerase theta) can exploit this repair deficiency to make pancreatic cancer cells more sensitive to cisplatin, a commonly used genotoxic chemotherapeutic. The increased toxicity was not seen in a non-transformed pancreatic cell line. We also found that while ART558 sensitizes pancreatic cancer cells to cisplatin, it also sensitized non-transformed pancreatic cancer cells.

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.

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.

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.

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.

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

CCS1477 is currently in Phase I/II clinical trials in AML, Non-Hodgkin lymphoma (including B-cell lymphoma) and multiple myeloma. (NCT04068597).

P1/2, N=250, Ongoing, CellCentric Ltd

In this issue of Cancer Discovery, Welti and colleagues demonstrate a positive correlation between the expression of the histone acetyltransferase paralogs CBP and p300 with increased androgen receptor (AR) signaling and androgen deprivation therapy resistance in advanced prostate cancer. CCS1477, a selective inhibitor of p300/CBP bromodomain, disrupts AR- and MYC-regulated gene expression, suppresses tumor growth in vivo in multiple castration-resistant prostate cancer xenograft models, and modulates biomarker expression in early clinical evaluation, providing a novel therapeutic approach for AR-addicted advanced prostate cancer.See related article by Welti et al., p. 1118.

P1/2, N=200, Recruiting, CellCentric Ltd. | Trial primary completion date: Dec 2020 --> Mar 2021

Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced PC.