Abstract 5783: HY809382, a PRC2 degrader with best-in-class properties, demonstrates efficacy across multiple tumors and overcomes EZH2 inhibitor clinical resistance caused by EZH2 genetic mutations

Abstract The dysregulation of Polycomb repressive complex 2 (PRC2) is implicated in tumorigenesis across a spectrum of cancers, such as prostate cancer, non-small cell lung cancer, ​endometrial carcinoma, ovarian cancer, clear cell renal cell carcinoma and hematological malignancies. Furthermore, aberrant PRC2 activity is closely associated with tumor immune evasion and the development of therapy resistance, thereby influencing clinical outcomes. Given its critical role in tumor initiation and progression, the core PRC2 subunits EZH2 and EED have emerged as promising therapeutic targets. Among various EZH2 inhibitors under development, Tazemetostat (Tazverik) was the first to received FDA approval for the treatment of follicular lymphoma (FL) and epithelioid sarcoma (ES). Despite this progress, new challenges have emerged, including acquired resistance through EZH2 mutations and limited efficacy in tumors due to EZH1 compensatory mechanisms. Degradation of EED disrupts the assembly, stability, and activity of PRC2 complex, offering potential advantages over merely inhibiting EZH2 catalytic function. HY809382 is a potent and selective PRC2 degrader that targeted the EED subunit, designed with superior drug-like properties compared to existing EZH2 and EED inhibitors. HY809382 potently inhibited the proliferation of multiple tumor cell lines in vitro, including prostate cancer, endometrial carcinoma and gastric adenocarcinoma. Under identical experimental conditions, HY809382 exhibited greater potency than both PF-06821497 (an EZH2 inhibitor) and APG-5918 (an EED inhibitor). Once-daily oral administration of HY809382 demonstrated significant and dose-dependent tumor growth inhibition in xenograft models of prostate cancer, endometrial carcinoma, and gastric adenocarcinoma. Furthermore, HY809382 combined with enzalutamide synergistically suppressed tumor growth in a castration-resistant prostate cancer xenograft model. Clinically identified EZH2 mutations confer resistance to FDA-approved EZH2 inhibitors, whereas HY809382 remained effective in both cellular and in vivo xenograft models. Collectively, these data support HY809382 as a promising best-in-class PRC2 degrader candidate, warranting further development for the treatment of tumors exhibiting clinical resistance to EZH2 inhibitors. Citation Format: Xin Li, Weixing Zhu, Ruwei Wang, Zengrong Li, Liming Zhang, Lei Chen, Sai Yang, Feng Xu, Qian Ma, Huangtao Jin, Xiaotian Huang, Ting Zhang, Xing Yu, Ming Weng, Xiaoxiao Wang, Xiaohong Hou, Manli Hu, Tingting Dai, Ruowen Zhang, Juan Du. HY809382, a PRC2 degrader with best-in-class properties, demonstrates efficacy across multiple tumors and overcomes EZH2 inhibitor clinical resistance caused by EZH2 genetic mutations [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 5783.