inobrodib (CCS1477)

Upstream regulators of the homologous recombination (HR) repair pathway are promising targets for overcoming temozolomide (TMZ) resistance. Both compounds inhibited H3K27Ac and were detectable in orthotopic tumors by LC-MS/MS and significantly extended survival alone and in combination with TMZ. These findings suggest that the RBBP4/p300-axis is a key regulator of HR-mediated repair of TMZ-induced DSBs, and inhibition by either CCS1477 or NEO2734 may be beneficial as monotherapy, but further studies are needed to determine the benefit of combining these agents with TMZ.

We find that use of the dual histone acetyltransferase p300/CBP bromodomain inhibitor CCS1477 (inobrodib), together with venetoclax and gilteritinib, virtually eliminates leukemia stem cells in an aggressive preclinical model of DNMT3A/FLT3-mutant AML by impairing pro-oncogenic survival and proliferation factors to effectively block leukemogenesis. This work identifies potential clinical utility of a targeted, triplet combination therapy for treatment of AML.

P2, N=100, Recruiting, CellCentric Ltd. | Not yet recruiting --> Recruiting

Compared to CCS1477, it shows comparable in vivo efficacy in the OPM-2 xenograft model and demonstrates more potent antitumor activity in the 22RV1 xenograft model, with tumor growth inhibition values of 56.2% and 72.8%, respectively. Overall, CZL-077 is a promising candidate for the treatment of human cancer as a p300/CBP BRD inhibitor.

By selectively targeting EP300, CCS1477 orchestrates a dual pro-death mechanism involving both intrinsic apoptosis execution and PINK1-driven mitochondrial clearance, resulting in significant inhibition of diffuse large B-cell lymphoma pathogenesis.

P1/2, N=220, Completed, CellCentric Ltd. | Active, not recruiting --> Completed

P2, N=100, Not yet recruiting, CellCentric Ltd.

P1/2, N=350, Active, not recruiting, CellCentric Ltd. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Dec 2024 --> Aug 2025

By reducing PD-L1 expression and modulating the immunosuppressive TME, CCS1477 creates a more favorable environment for tumor-infiltrating lymphocytes, significantly enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Notably, these effects were observed in both prostate cancer and melanoma models, underscoring the broad therapeutic potential of p300/CBP bromodomain inhibition in improving ICB outcomes.

Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/ p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.

P1/2, N=250, Recruiting, CellCentric Ltd. | Trial completion date: Jun 2025 --> Mar 2027 | Trial primary completion date: Jun 2025 --> Mar 2027

CLP endopeptidase inhibition overcame conventional and novel drug resistance, induced apoptosis in primary samples, showed efficacy in vivo, and could be achieved with the clinically relevant agent inobrodib. Finally, regimens combining a CLPP and proteasome inhibitor showed enhanced efficacy, as did combinations with inhibitors of intermediary metabolism and autophagy. Taken together, our data indicate that CLPP is a key contributor to transformed plasma cells, a novel mediator of high-risk behavior, and a legitimate target for myeloma therapy whose inhibitors could be rationally combined with current therapeutics to improve outcomes.