Abstract 4488: Targeting non-canonical PRC2 functions via small-molecule degradation: A novel therapeutic strategy for prostate cancer and other solid tumors.

Abstract Background: The Polycomb Repressive Complex 2 (PRC2) is a key epigenetic regulator responsible for histone H3 lysine 27 methylation (H3K27me3) and is implicated in essential cellular processes. However, its core components, EZH2 and EED, also exert extensive non-conventional functions through protein-protein interactions (PPIs) with other proteins, independent of its methyltransferase activity. Aberrant activation or overexpression of PRC2 components, particularly EZH2, drives oncogenesis and tumor progression in a variety of cancers. While several enzymatic inhibitors targeting PRC2 components (EZH2, EED, and EZH1/2) have been developed, their therapeutic efficacy remains limited, particularly in solid tumors, where clinical responses are often modest and transient. Notably, emerging evidence from KO/KD models, as well as PROTACs underscores the non-canonical, non-enzymatic functions in tumor maintenance, positioning PRC2 as a more effective therapeutic target. PROTAC-based degraders targeting these functions show promise but are hampered by poor permeability and stability. We developed novel small-molecule PRC2 degraders to overcome these limitations. Methods: Small molecular lead candidates CTS3353 and CTS3952 were evaluated for their -PRC2 degradation efficacy, and in vitro antiproliferative effects across multiple cancer cell lines (e.g., mCRPC cell 22Rv1, DLBCL Karpas422). Pharmacokinetic and in vivo efficacy were performed in cell-derived xenograft (CDX) models of prostate cancer (especially in mCRPC) and DLBCL. Results: CTS3353 and CTS3952 achieved potent PRC2 downregulation through complex disruption in 22Rv1 and Karpass422 cells. They exhibited superior cell permeability and metabolic stability compared to conventional PROTAC-based degraders. Both compounds induced sustained suppression of PRC2 components, leading to potent anti-proliferative effects. In mCRPC CDX models, CTS3353 and CTS3952 achieved robust antitumor activity, reducing tumor burden and improving survival without observable systemic toxicity. These effects were attributed to the disruption of PRC2’s non-canonical functions rather than its histone methyltransferase activity. Conclusions: Our findings highlight the therapeutic potential of targeting the non-enzymatic functions of PRC2 through small-molecule degradation. CTS3353 and CTS3952 represent a new class of potent and bioavailable PRC2 degraders with promising preclinical efficacy in solid tumor models such as mCRPC and TNBC. This strategy provides a foundation for next-generation PRC2-directed cancer therapies beyond enzymatic inhibition. Citation Format: Hui Shi, Xinyue Duan, Jiaxin Huang, Qiugeng Ouyang, Xingnian Fu, Guoliang Xu, Haiping Wu. Targeting non-canonical PRC2 functions via small-molecule degradation: A novel therapeutic strategy for prostate cancer and other solid tumors 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 4488.