Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression

  • J Med Chem. 2021 Oct 14;64(19):14540-14556. doi: 10.1021/acs.jmedchem.1c01059.
Rohan Kalyan Rej ,  Changwei Wang ,  Jianfeng Lu ,  Mi Wang ,  Elyse Petrunak ,  Kaitlin P Zawacki ,  Donna McEachern ,  Chao-Yie Yang  1 ,  Lu Wang ,  Ruiting Li ,  Krishnapriya Chinnaswamy ,  Bo Wen ,  Duxin Sun ,  Jeanne A Stuckey ,  Yunlong Zhou  2 ,  Jianyong Chen  2 ,  Guozhi Tang  2 ,  Shaomeng Wang
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 2. Ascentage Pharma Group, Suzhou, Jiangsu 215216, China.
PMID: 34613724 DOI: 10.1021/acs.jmedchem.1c01059
Abstract

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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