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 ESR1^Y537S 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.

中文翻译：

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发现 ERD-1233 作为一种有效且口服有效的雌激素受体 PROTAC 降解剂治疗 ER+ 人乳腺癌


尽管已经开发了用于治疗雌激素受体α （ERα） 阳性人乳腺癌的高效疗法，但对当前疗法的临床耐药性需要开发新的治疗策略。在此，我们报道了 ERD-1233 作为使用 PROTAC 技术设计的有效且口服有效的 ERα 降解剂的发现。ERD-1233 是基于 Lasofoxifene 作为 ER 结合部分和新型 cereblon 配体，通过对接头的广泛优化而开发的。ERD-1233 在体外有效降低 ERα 蛋白，并在小鼠和大鼠中实现优异的口服生物利用度。口服 ERD-1233 可有效降低 ER+ 肿瘤中的 ER 蛋白，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 ESR1^Y537S 突变模型中实现强肿瘤生长抑制。我们的数据表明，ERD-1233 是一种很有前途的 ER PROTAC 降解剂，作为治疗 ER+ 人乳腺癌的新疗法进行广泛评价。