| Literature DB >> 32580550 |
Rohan Kalyan Rej1,2, Changwei Wang1,2, Jianfeng Lu1,2, Mi Wang1,2, Elyse Petrunak3, Kaitlin P Zawacki1,2, Donna McEachern1,2, Ester Fernandez-Salas1,2, Chao-Yie Yang1,2, Lu Wang1,4, Ruiting Li1,4, Krishnapriya Chinnaswamy3, Bo Wen1,4, Duxin Sun1,4, Jeanne Stuckey1,3, Yunlong Zhou5, Jianyong Chen5, Guozhi Tang5, Shaomeng Wang6.
Abstract
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 IC50 value of 0.2 nM and inhibits cell growth with IC50 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.Entities:
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Year: 2020 PMID： 32580550 PMCID： PMC8859984 DOI： 10.1021/acs.jmedchem.0c00479
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446