Abstract 1036: Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED)

Abstract

Abstract Embryonic ectoderm development (EED) is a key component of the polycomb repressive complex 1 (PRC1) and PRC2 and targeting EED by an allosteric mechanism represents a potentially attractive strategy for the treatment of human cancers. We report herein the discovery of a new class of highly potent and efficacious small-molecule EED inhibitors, as exemplified by UM-EEDi-5285. UM-EEDi-5285 binds to EED protein with a low nanomolar affinity and achieves IC50 values of < 1 nM in inhibition of cell growth in Pfeiffer and Karpas-422 lymphoma cell lines carrying an EZH2 mutation. UM-EEDi-5285 is capable of achieving complete and durable tumor regression in the KARPAS-422 xenograft model in mice at well-tolerated dose-schedules. The co-crystal structure of UM-EEDi-5285 in a complex with EED provides the structural basis for their high-affinity interaction. UM-EEDi-5285 is arguably the most potent and efficacious EED inhibitor reported to date. UM-EEDi-5285 is a promising lead compound for advanced preclinical development studies. Citation Format: Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang. Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1036.