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

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.

胚胎外胚层发育蛋白（Embryonic ectoderm development, EED）是人类癌症及其他疾病极具潜力的治疗靶点。本文报道了一类强效且高效的EED抑制剂的发现历程：通过对此前报道的EED抑制剂进行构象限制，我们获得了活性优异的先导化合物；对该先导化合物开展进一步优化后，得到了活性极强的EED抑制剂。其中最优化合物EEDi-5273与EED结合的半最大抑制浓度（IC50）为0.2 nM，对KARPAS422细胞增殖的半最大抑制浓度为1.2 nM。该化合物展现出优异的药代动力学（PK）与吸收-分布-代谢-排泄（ADME）特性，口服给药后可在KARPAS422异种移植模型中实现完全且持久的肿瘤消退，且未观察到任何毒性迹象。两款强效EED抑制剂与EED的共晶结构为其高亲和力结合提供了坚实的结构基础。EEDi-5273是一款极具潜力的EED抑制剂，可进一步推进针对人类癌症及其他人类疾病的高级临床前开发。