Rohan Kalyan Rej,◆ Changwei Wang,◆ Jianfeng Lu, Mi Wang, Elyse Petrunak, Kaitlin P. Zawacki, Donna McEachern, Chao-Yie Yang, Lu Wang, Ruiting Li, Krishnapriya Chinnaswamy, Bo Wen,* Duxin Sun, Jeanne A. Stuckey, Yunlong Zhou, Jianyong Chen, Guozhi Tang, and Shaomeng Wang*
◆R.K.R. and C.W. contributed equally

Journal of Medicinal Chemistry 2021
Publication Date (Web):October 6, 2021
DOI: 10.1021/acs.jmedchem.1c01059 


Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC50 value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases.


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