发现 EEDi-5273 是一种效力极高的口服有效 EED 抑制剂，能够实现完全和持久的肿瘤消退。
Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
Ascentage Pharma Group, Suzhou, Jiangsu 215216, China.
出版信息
J Med Chem. 2021 Oct 14;64(19):14540-14556. doi: 10.1021/acs.jmedchem.1c01059. Epub 2021 Oct 6.
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 IC value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC 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（EED）是治疗人类癌症和其他疾病的有前途的治疗靶点。本文报道了对 EED 具有极高活性和效力的抑制剂的发现。通过对先前报道的 EED 抑制剂进行构象限制，我们获得了一种有效的先导化合物。进一步优化该先导化合物得到了对 EED 具有极高活性的抑制剂。最佳化合物 EEDi-5273 与 EED 的 IC 值为 0.2 nM，并以 IC 值为 1.2 nM 抑制 KARPAS422 细胞的生长。它表现出优异的 PK 和 ADME 特性，其口服给药可导致 KARPAS422 异种移植模型中的肿瘤完全和持续消退，且没有毒性迹象。两种强效 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 是一种很有前途的 EED 抑制剂，可进一步进行临床前开发，用于治疗人类癌症和其他人类疾病。
Zotero 插件