EEDi-5285：一种效力极强、功效极高且可口服的胚胎外胚层发育小分子抑制剂。
EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development.
机构信息
Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
出版信息
J Med Chem. 2020 Jul 9;63(13):7252-7267. doi: 10.1021/acs.jmedchem.0c00479. Epub 2020 Jun 24.
Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC value of 0.2 nM and inhibits cell growth with IC values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date.
抑制胚胎外胚层发育（EED）是一种新的癌症治疗策略。在此，我们报告了 EEDi-5285 的发现，它是一种非常有效、高效且可口服的 EED 抑制剂。EEDi-5285 与 EED 蛋白的结合 IC 值为 0.2 nM，并分别在携带 EZH2 突变的 Pfeiffer 和 KARPAS422 淋巴瘤细胞系中，IC 值为 20 pM 和 0.5 nM 时抑制细胞生长。EEDi-5285 与 EED 的结合比 EED226 强约 100 倍，在 KARPAS422 细胞系中抑制细胞生长的效力比 EED226 强约 300 倍。EEDi-5285 具有出色的药代动力学特性，在 KARPAS422 异种移植模型中经口服给药可完全和持久地抑制肿瘤生长。EEDi-5285 与 EED 的复合物的共晶结构定义了它们高结合亲和力的精确结构基础。EEDi-5285 是迄今为止报道的最有效、高效的 EED 抑制剂。
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