State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2020 Nov 15;206:112689. doi: 10.1016/j.ejmech.2020.112689. Epub 2020 Aug 2.
Estrogen receptor alfa (ERα) is expressed in approximate 70% of breast cancer (BC) which is the most common malignancy in women worldwide. To date, the foremost intervention in the treatment of ER positive (ER+) BC is still the endocrine therapy. However, resistance to endocrine therapies remains a major hurdle in the long-term management of ER + BC. Although the mechanisms underlying endocrine resistance are complex, cumulative evidence revealed that ERα still plays a critical role in driving BC tumor cells to grow in resistance state. Fulvestrant, a selective estrogen receptor degrader (SERD), has moved to first line therapy for metastatic ER + BC, suggesting that removing ERα would be a useful strategy to overcome endocrine resistance. Proteolysis-Targeting Chimera (PROTAC) technology, an emerging paradigm for protein degradation, has the potential to eliminate both wild type and mutant ERα in breast cancer cells. Excitingly, ARV-471, an ERα-targeted PROTAC developed by Arvinas, has been in phase 1 clinical trials. In this review, we will summarize recent progress of ER-targeting PROTACs from publications and patents along with their therapeutic opportunities for the treatment of endocrine-resistant BC.
雌激素受体 alpha（ERα）在大约 70%的乳腺癌（BC）中表达，BC 是全球女性中最常见的恶性肿瘤。迄今为止，治疗雌激素受体阳性（ER+）BC 的主要干预措施仍然是内分泌治疗。然而，对内分泌治疗的耐药性仍然是 ER+BC 长期管理中的一个主要障碍。尽管内分泌耐药的机制很复杂，但越来越多的证据表明，ERα 在驱动 BC 肿瘤细胞进入耐药状态方面仍然起着关键作用。氟维司群是一种选择性雌激素受体降解剂（SERD），已被用于转移性 ER+BC 的一线治疗，这表明去除 ERα 将是克服内分泌耐药的一种有效策略。蛋白水解靶向嵌合体（PROTAC）技术是一种新兴的蛋白降解方法，有可能在乳腺癌细胞中同时消除野生型和突变型 ERα。令人兴奋的是，Arvinas 公司开发的 ER 靶向 PROTAC 药物 ARV-471 已进入 1 期临床试验。在这篇综述中，我们将总结最近从出版物和专利中获得的 ER 靶向 PROTAC 的进展及其在治疗内分泌耐药性 BC 方面的治疗机会。
