In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1036-1036
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 & lt; 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.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-1036
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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