Abstract 4484: Characterization and pre-clinical development of LG-CBP/p300 inhibitor, a potent and selective bromodomain inhibitor of CBP/p300.

Abstract Background Acute Myeloid Leukemia (AML) is a heterogeneous hematologic malignancy characterized by uncontrolled proliferation and impaired differentiation of myeloid progenitors. Despite advances in targeted and combination therapies, relapse and resistance remain major clinical challenges, underscoring the need for novel therapeutic approaches. Epigenetic dysregulation is a hallmark of AML, with transcriptional co-activators CBP (CREBBP) and p300 (EP300) emerging as key regulators of leukemogenesis. These histone acetyltransferases (HATs) catalyze acetylation of histone H3 lysine 27 (H3K27), promoting open chromatin and transcriptional activation of genes involved in cell proliferation and differentiation. Aberrant CBP/p300 activity sustains oncogenic transcriptional programs driven by factors such as MYC and MYB. Preclinical studies have demonstrated that pharmacologic inhibition of CBP/p300 suppresses leukemic cell growth and reduces leukemia-initiating potential, supporting CBP/p300 as a promising therapeutic target in AML. In this study, we evaluated the antileukemic efficacy and molecular mechanism of a selective CBP/p300 inhibitor in AML models to assess its translational potential. Method The antileukemic activity of the LG-CBP/p300 inhibitor was assessed in AML cell lines and in vivo mouse models. Cell viability was measured using CellTiter-Glo®. H3K27ac levels were analyzed by flow cytometry. The expression of MYC and MYB were quantified by reverse transcription quantitative PCR (RT-qPCR) and western blot. Pharmacodynamic and efficacy studies were conducted in both subcutaneous and disseminated xenograft AML mouse models. Result The LG-CBP/p300 inhibitor exhibited potent anti-proliferative activity in AML cell lines, with IC50 values in the nanomolar range. The compound was effective across AML cell lines regardless of the presence or absence of common AML-associated mutations. Target engagement was confirmed by concentration-dependent reductions in H3K27ac levels and downregulation of MYC and MYB mRNA expression. In in vivo studies using AML cell lines resistant to venetoclax, this inhibitor significantly suppressed tumor growth in a dose-dependent manner in a subcutaneous xenograft model. Moreover, in a systemic AML mouse model, it reduced leukemia burden and prolonged survival. Conclusions Selective inhibition of CBP/p300 exerts potent antileukemic effects by regulating multiple oncogenes. The LG-CBP/p300 inhibitor represents a promising epigenetic therapeutic strategy for AML with strong translational potential. Citation Format: Sinae Lee, Yuna Chang, Ik Sun Kim, Sung Woong Jang, Rira Kim, Gyungah Pak, Bitna Oh, Byung Gyu Kim, Sugyeong Woo. Characterization and pre-clinical development of LG-CBP/p300 inhibitor, a potent and selective bromodomain inhibitor of CBP/p300 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4484.