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

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 s

SUBMITTER: Rej RK 

PROVIDER: S-EPMC8862192 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature