Abstract 447: Preclinical development and characterization of IACS-16559, a dual bromodomain inhibitor of CBP/EP300, and its potential in AML subtypes

Abstract Paralogs CBP and EP300 are transcriptional co-regulators, with a mechanism of action involving regulation of chromatin accessibility, direct acetylation of master transcriptional factors and bridging enhancers to activated promoters. They possess both reader and writer of the histone code due to the bromodomain and histone acetyltransferase domain, respectively. Aberrant transcription in cancer can occur at multiple stages, contributing to proliferation, therapeutic resistance, and escape from induced cell death, making it a good target for therapeutic intervention. Clinical validation of bromodomain inhibition of paralogs CBP and EP300 is undergoing in multiple clinical trials, including both hematological diseases and solid tumors, using EP31670, CCS1477 and TT125-802, while selective CBP or EP300 inhibition is being explored preclinically. We recently developed a dual bromodomain inhibitor for CBP and EP300, IACS-16559 with selectivity over BRD4, pharmacokinetic properties showing low clearances, high oral exposures and predicted QD dosing in human. IACS-16559 toxicity profile in rats and dogs was in line with previous reports for dual CBP/EP300 bromodomain inhibition. Repeat dose studies in rats and dogs of IACS-16559 was tolerated, with dose-dependent changes affecting bone marrow and lymphoid tissues, testes, GI tract at high doses. All the toxicology findings were reversable once the drug treatment is discontinued, and the animals allowed to recover. Given the potential for anticancer activity mediated by dual CBP/EP300 inhibition, we evaluated the response in selected subtypes of AML, both in vitro and in vivo. Single agent inhibition prolongs survival of the mice bearing orthotopic leukemia xenografts driven by several alterations, such as AML1-ETO, MLL-AF9, NPM1c, RUNX1mut. Mechanistically, CBP/EP300 dual inhibition caused disruption of the MYC and MYB oncogenic network in multiple models, required for the AML proliferation. Interestingly, the combination of IACS-16559 and MLL-Menin inhibition demonstrated synergistic effects in vivo with the OCI-AML3 (NPM1c) model, significantly prolonging the survival of experimental animals. However, in contrast, long-term treatment in the MLL-AF9 (MOLM14) model resulted in antagonistic effects. These findings underscore the complexities of combinatorial therapeutic development and emphasize the critical need for careful selection of robust therapeutic combinations and consideration of the genetic background in the target disease. Citation Format: Ciro Zanca, Michael Soth, Ajay Saw, Uttara Saran, Guang Gao, Jason Gay, Ningping Feng, Christopher Bristow, Joseph Marszalek, Kunal Rai, Virginia Giuliani, Tim Heffernan. Preclinical development and characterization of IACS-16559, a dual bromodomain inhibitor of CBP/EP300, and its potential in AML subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 447.