Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
SK Life Science Laboratories, 2500 Renaissance Blvd, King of Prussia, Pennsylvania 19406, United States.
J Med Chem. 2024 Nov 14;67(21):19010-19037. doi: 10.1021/acs.jmedchem.4c01521. Epub 2024 Nov 1.
Despite the development of highly effective therapies for the treatment of estrogen receptor α (ERα)-positive human breast cancer, clinical resistance to current therapies requires the development of novel therapeutic strategies. Herein, we report the discovery of ERD-1233 as a potent and orally efficacious ERα degrader designed using the PROTAC technology. ERD-1233 was developed based on Lasofoxifene as the ER binding moiety and a novel cereblon ligand through extensive optimization of the linker. ERD-1233 potently and effectively reduces the ERα protein in vitro and achieves excellent oral bioavailability in mice and rats. Oral administration of ERD-1233 effectively reduces ER protein in ER+ tumors and achieves tumor regression in the ER wild-type MCF-7 xenograft tumor model and strong tumor growth inhibition in the mutated model in mice. Our data demonstrate that ERD-1233 is a promising ER PROTAC degrader for extensive evaluation as a new therapy for the treatment of ER+ human breast cancer.
尽管已经开发出了针对治疗雌激素受体α（ERα）阳性人乳腺癌的高效疗法，但目前疗法的临床耐药性仍需要开发新的治疗策略。在此，我们报告了 ERD-1233 的发现，它是一种使用 PROTAC 技术设计的强效、口服有效的 ERα 降解剂。ERD-1233 是基于拉索昔芬（Lasofoxifene）作为 ER 结合部分和一种新型的 cereblon 配体，通过对连接子进行广泛优化而开发的。ERD-1233 能够在体外有效地降低 ERα 蛋白水平，并在小鼠和大鼠中实现优异的口服生物利用度。口服给予 ERD-1233 能够有效地降低 ER+肿瘤中的 ER 蛋白水平，并在 ER 野生型 MCF-7 异种移植肿瘤模型中实现肿瘤消退，在小鼠的突变模型中实现强烈的肿瘤生长抑制。我们的数据表明，ERD-1233 是一种很有前途的 ER PROTAC 降解剂，值得进一步评估，作为治疗 ER+人乳腺癌的新疗法。
