Abstract 6271: Discovery of BR1733 for the treatment of SWI/SNF deficient or highly vascularized solid tumor

Abstract Polycomb repressive complex 2 (PRC2) catalyze the writing of H3K27me3 epigenetic marker and suppresses the expression of genes including tumor suppressors. Activation mutation of EZH2, the catalytic subunit of the PRC2 complex, drives the progression of tumors such as DLBCL. The embryonic ectoderm development (EED) protein acts as the scaffolding and H3K27me3-binding subunit of PRC2 and is essential for its activity. We have developed potent, selective, and orally bioavailable EED inhibitor BR1733. BR1733 blocks the interaction between EED and H3K27me3, and inhibits catalytic activity of PRC2. BR1733 showed superior PK profile across species and exhibited tumor growth inhibition against several B cell lymphoma CDX models. Indication expansion studies demonstrated that BR1733 could inhibit solid tumors with SWI/SNF loss-of-function mutation only when both CDKN2A and TET1 are expressed. BR1733 also inhibited tumor angiogenesis and showed tumor growth inhibition in several CDX models of highly vascularized solid tumors such as HCC and RCC. BR1733 is currently in Phase I clinical trials. Citation Format: Xinghao Wang, Shichao Ma, Min (Bella) Xie, Lele Wang, Yajun Wang, Song Zhang, Sheng Chen, Lynette Zhang, Yongqi Zhou, Mengxi Zhao, Dandan Li, Guobin Li, Xiao Fan, Hailong Zhang. Discovery of BR1733 for the treatment of SWI/SNF deficient or highly vascularized solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6271.