Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.

临床验证靶向雌激素受体α (ERα) 通路是治疗 ER+ 乳腺癌的有效手段。在这里，我们展示了一种 VHL 靶向和口服生物可利用的蛋白水解靶向嵌合体 (PROTAC) ERα 降解剂的开发。使用该 PROTAC 进行的体外研究表明，在 ER+ 乳腺癌细胞系中具有出色的 ERα 降解作用和 ER 拮抗作用。然而，在体内给予该化合物后，我们观察到体外-体内脱节。 ERα 体内降解低于基于体外数据的预期。对最大降解减少的潜在原因的调查表明，PROTAC 连接体的代谢不稳定性会产生与完整 PROTAC 竞争与 ERα 结合的代谢物，从而限制降解。这一观察结果强调了对代谢稳定的 PROTAC 的要求，以确保最大功效，因此连接子的优化应该是设计 PROTAC 时的一个关键考虑因素。