Purpose: Estrogen Receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR or PI3K inhibitors is now a central strategy for the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed. Experimental design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, potent small molecule PROteolysis-TArgeting Chimera (PROTAC®) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition. Results: Vepdegestrant induced ≥90% degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in-vitro and achieved significant tumor growth inhibition (TGI) (87-123%) in MCF7 orthotopic xenograft models, better than the ET agent fulvestrant (31-80% TGI). In the hormone-independent ER Y537S patient derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regressions and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib, the mTOR inhibitor everolimus, and the PI3K inhibitors alpelisib and inavolisib. Conclusions: Vepdegestrant achieved greater ER degradation in-vivo compared to fulvestrant, which correlated with improved tumor growth inhibition, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

中文翻译：

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口服雌激素受体 PROTAC® vepdegestrant (ARV-471) 在临床前 ER+ 乳腺癌模型中作为单一疗法以及与 CDK4/6 或 PI3K/mTOR 通路抑制剂联合使用均非常有效


目的：雌激素受体 (ER) α 信号传导是 ER 阳性 (ER+)/人表皮生长因子受体 2 阴性 (HER2-) 乳腺癌的已知驱动因素。目前，将氟维司群等内分泌治疗 (ET) 与 CDK4/6、mTOR 或 PI3K 抑制剂相结合是治疗 ER+ 晚期乳腺癌的核心策略。然而，ESR1 突变导致的 ER 抑制效果不佳和耐药性表明需要新的疗法。实验设计：一项药物化学活动确定了 vepdegestrant (ARV-471)，这是一种选择性的、口服生物可利用的、有效的小分子 PROteothesis-Targeting Chimera (PROTAC®) ER 降解剂。我们使用生化和细胞内靶标结合测定来证明 vepdegestrant 的作用机制，并使用 ESR1 野生型和突变型 ER+ 临床前乳腺癌模型来证明 ER 降解介导的肿瘤生长抑制。结果：Vepdegestrant 诱导野生型 (WT) 和突变型 ER 降解 ≥90%，在体外抑制 ER 依赖性乳腺癌细胞系增殖，并在 MCF7 原位异种移植物中实现显着的肿瘤生长抑制 (TGI) (87-123%)模型，优于 ET 剂氟维司群 (31-80% TGI)。在激素非依赖性 ER Y537S 患者来源的异种移植 (PDX) 乳腺癌模型 ST941/HI 中，vepdegestrant 实现了肿瘤消退，并且在 ST941/HI/PBR palbociclib 耐药模型 (102% TGI) 中也同样有效。 Vepdegestrant 与 CDK4/6 抑制剂 palbociclib、abemaciclib 和 ribociclib、mTOR 抑制剂依维莫司以及 PI3K 抑制剂 alpelisib 和 inavolisib 联合使用，可诱导肿瘤稳健消退。 结论：与氟维司群相比，Vepdegestrant 在体内实现了更大的 ER 降解，这与改善的肿瘤生长抑制相关，表明 vepdegestrant 可能是 ER+/HER2- 乳腺癌患者更有效的骨干 ET。