inobrodib (CCS1477)

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.

Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD+ AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML.