Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Curr Opin Pharmacol. 2010 Dec;10(6):620-8. doi: 10.1016/j.coph.2010.09.007.
Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the Selective Estrogen Receptor Modulators (SERMs) tamoxifen and raloxifene, so called for their ability to function as ER agonists or antagonists depending on the tissue in which they operate. These mechanistic insights have had a significant impact on the discovery of second generation SERMs, some of which are in late stage clinical development for the treatment/prevention of breast cancer as well as other estrogenopathies. In addition to the SERMs, however, have emerged the Selective Estrogen Degraders (SERDs), which as their name suggests, interact with and facilitate ER turnover in cells. One drug of this class, fulvestrant, has been approved as a third line treatment for ER-positive metastatic breast cancer. Whereas the first generation SERMs/SERDs were discovered in a serendipitous manner, this review will highlight how our understanding of the molecular pharmacology of ER ligands has been utilized in the development of the next generation of SERMs/SERDs, some of which are likely to have a major impact on the pharmacotherapy of breast cancer.
近年来，我们对雌激素受体 (ER) 配体药理作用的分子机制的理解有了很大的发展。这些知识主要来自对选择性雌激素受体调节剂 (SERM) 他莫昔芬和雷洛昔芬作用机制的详细剖析，之所以这样命名是因为它们能够根据作用的组织而充当 ER 激动剂或拮抗剂。这些机制上的见解对第二代 SERM 的发现产生了重大影响，其中一些正在进行晚期临床开发，用于治疗/预防乳腺癌和其他雌激素疾病。然而，除了 SERM 之外，还出现了选择性雌激素降解剂 (SERD)，顾名思义，它们与细胞中的 ER 相互作用并促进其周转。该类药物中的一种，氟维司群，已被批准作为 ER 阳性转移性乳腺癌的三线治疗药物。虽然第一代 SERM/SERM 是偶然发现的，但本综述将重点介绍我们对 ER 配体分子药理学的理解如何应用于下一代 SERM/SERM 的开发，其中一些可能对乳腺癌的药物治疗产生重大影响。
