Zlotos Darius P, Kronenberger Thales, Laufer Stefan A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City 11835, Cairo, Egypt.
Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.
Pharmaceutics. 2022 Dec 26;15(1):67. doi: 10.3390/pharmaceutics15010067.
Hormone-dependent cancers, such as certain types of breast cancer are characterized by over-expression of estrogen receptors (ERs). Anticancer drug conjugates combining ER ligands with other classes of anticancer agents may not only benefit from dual action at both anti-cancer targets but also from selective delivery of cytotoxic agents to ER-positive tumor cells resulting in less toxicity and adverse effects. Moreover, they could also take advantage of overcoming resistance typical for anti-hormonal monotherapy such as tamoxifen. In this review, we discuss the design, structures and pharmacological effects of numerous series of drug conjugates containing ER ligands such as selective ER modulators (tamoxifen, 4-hydroxytamoxifen, endoxifen), selective ER degraders (ICI-164384) and ER agonists (estradiol) linked to diverse anti-cancer agents including histone-deacetylase inhibitors, DNA-alkylating agents, antimitotic agents and epidermal growth factor receptor inhibitors.
激素依赖性癌症，如某些类型的乳腺癌，其特征在于雌激素受体（ERs）的过度表达。将ER配体与其他类别的抗癌剂相结合的抗癌药物偶联物不仅可能受益于在两个抗癌靶点的双重作用，还可能受益于细胞毒性剂向ER阳性肿瘤细胞的选择性递送，从而降低毒性和不良反应。此外，它们还可以利用克服抗激素单一疗法（如他莫昔芬）典型的耐药性。在这篇综述中，我们讨论了众多含有ER配体的药物偶联物系列的设计、结构和药理作用，这些配体包括选择性ER调节剂（他莫昔芬、4-羟基他莫昔芬、依西美坦）、选择性ER降解剂（ICI-164384）和ER激动剂（雌二醇），它们与多种抗癌剂相连，包括组蛋白去乙酰化酶抑制剂、DNA烷基化剂、抗有丝分裂剂和表皮生长因子受体抑制剂。
