Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
J Med Chem. 2023 Jul 13;66(13):8339-8381. doi: 10.1021/acs.jmedchem.3c00136. Epub 2023 Jun 28.
Estrogen receptor alpha (ERα) is a well-established therapeutic target for the treatment of ER-positive (ER+) breast cancers. Despite the tremendous successes achieved with tamoxifen, a selective ER modulator, and aromatase inhibitors (AIs), resistance to these therapies is a major clinical problem. Therefore, induced protein degradation and covalent inhibition have been pursued as new therapeutic approaches to target ERα. This Perspective summarizes recent progress in the discovery and development of oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), and proteolysis targeting chimera (PROTAC) ER degraders. We focus on those compounds which have been advanced into clinical development.
雌激素受体 alpha（ERα）是治疗雌激素受体阳性（ER+）乳腺癌的既定治疗靶点。尽管他莫昔芬（一种选择性雌激素受体调节剂）和芳香酶抑制剂（AIs）取得了巨大成功，但对这些疗法的耐药性仍是一个主要的临床问题。因此，诱导蛋白降解和共价抑制已被作为针对 ERα 的新治疗方法进行探索。本观点总结了口服选择性雌激素受体降解剂（SERDs）、完全雌激素受体拮抗剂（CERANs）、选择性雌激素受体共价拮抗剂（SERCAs）和蛋白水解靶向嵌合体（PROTAC）ER 降解剂的发现和开发方面的最新进展。我们重点关注那些已进入临床开发阶段的化合物。
