Oncology R&D, AstraZeneca, Cambridge, UK.
Pharmaceutical Sciences, AstraZeneca, Cambridge, UK.
Commun Biol. 2024 May 13;7(1):563. doi: 10.1038/s42003-024-06238-x.
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.
靶向雌激素受体 alpha（ERα）途径在临床上被验证为治疗 ER+乳腺癌的有效手段。在这里，我们介绍了一种 VHL 靶向和口服生物可利用的蛋白水解靶向嵌合体（PROTAC）降解剂 ERα 的开发。该 PROTAC 的体外研究表明，它在 ER+乳腺癌细胞系中具有优异的 ERα 降解和 ER 拮抗作用。然而，在体内给药后，我们观察到体外-体内的不匹配。与基于体外数据的预期相比，体内 ERα 的降解较低。对潜在的降低最大降解原因的调查表明，PROTAC 接头的代谢不稳定性会产生代谢物，这些代谢物与完整的 PROTAC 竞争与 ERα 结合，从而限制降解。这一观察结果强调了需要代谢稳定的 PROTAC 以确保最大疗效，因此在设计 PROTAC 时，优化接头应该是一个关键考虑因素。
