Abstract B117: Discovery of potent, selective, and orally bioavailable heterobifunctional EP300 degraders

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Abstract EP300 and CBP are closely related transcriptional coactivators possessing histone acetyltransferase (HAT) activity, playing essential roles in the regulation of gene expression, cell proliferation, and differentiation. Both are frequently dysregulated or overexpressed in various cancers. In normal tissues, EP300 and CBP can compensate for each other’s function. However, in cancers with CBP-deficiency, tumor cells become selectively dependent on EP300 for survival, creating a promising synthetic lethal therapeutic window. Despite this opportunity, developing EP300-selective inhibitors has been challenging due to the over 90% sequence identity between the HAT domains of EP300 and CBP. In this regard, targeted protein degradation (TPD) platform can provide potential opportunity to achieve selective degradation. Recent findings indicate that even subtle structural variations, such as a single surface residue near the binding interface or the positioning of a lysine, can amplify into significant differences in ternary complex stability and ubiquitination efficiency of proteolysis targeting chimera. To address the challenge of selectively targeting EP300 over CBP, we developed heterobifunctional degraders based on the TPD platform. Herein, we report the discovery of orally bioavailable EP300 degraders that achieve potent and selective degradation of EP300, robust anti-tumor efficacy, and minimal off-target effects on CBP, supporting their potential as highly promising therapeutics for EP300-dependent and CBP-deficient cancers. Structure-based in silico modeling, incorporating a ternary complex sampler, was employed to rationally design EP300-selective degraders that promote ternary complex formation and induce neo-protein–protein interactions (neo-PPI). The resulting Hanmi EP300 degraders demonstrated potent and selective EP300 degradation with minimal CBP engagement, as assessed by degradation assays including western blotting in HAP1 cells (HME04 Dmax 98%). Robust antitumor efficacy was observed in EP300-dependent or CBP-deficient cell lines (e.g. VCaP; HME04 GI50 4.5 nM), as well as in an in vivo xenograft model. These degraders exhibited orally bioavailable DMPK profiles, supporting their potential for clinical application. Mechanistic studies confirmed that Hanmi EP300 degraders induce degradation via the ubiquitin–proteasome system (UPS), as demonstrated by inhibition with neddylation and proteasome inhibitors. To assess degradation selectivity, global proteomic profiling was performed, revealing a favorable on-/off-target profile. In conclusion, the Hanmi degraders demonstrated potent and selective EP300 degradation with minimal impact on CBP, combined with promising antitumor activity in EP300-dependent cancer models. These preclinical findings suggest that the therapeutic potential of Hanmi EP300 degraders for EP300-dependent and CBP-deficient cancers. Citation Format: Yongtaek Lee, Sun Young Jang, SeokJong Kang, Ho Yeon Nam, Seongil Kang, Taegun Kim, Gunwoo Lee, Wonjong Lee, Hobin Im, Boram Kim, Yu-Yon Kim, Jooyun Byun, Haemin Chon, Young Gil Ahn. Discovery of potent, selective, and orally bioavailable heterobifunctional EP300 degraders [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B117.

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