Fan Meiyun, Rickert Emily L, Chen Lei, Aftab Syed A, Nephew Kenneth P, Weatherman Ross V
Department of Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA.
Breast Cancer Res Treat. 2007 May;103(1):37-44. doi: 10.1007/s10549-006-9353-2. Epub 2006 Oct 11.
Antiestrogens used for breast cancer therapy can be categorized into two classes that differ in their effect on estrogen receptor (ER) alpha stability. The selective estrogen receptor modulators (SERMs) stabilize ER alpha and the selective estrogen receptor downregulators (SERDs) cause a decrease in cellular ER alpha levels. A clinically relevant antiestrogen, GW7604, appears to work through a SERD-like mechanism, despite sharing the same molecular scaffold as 4-hydroxytamoxifen, a SERM. In order to investigate potential structural features of GW7604 responsible for SERD activity, GW7604 and two analogs were synthesized using a new, improved synthetic route and tested for their effects on ER alpha function and cell proliferation. The two analogs, which have an acrylamide or a methyl vinyl ketone replacing the acrylic acid group of GW7604, display lower binding affinity for ER alpha than GW7604, but show similar antagonism of estradiol-induced activation of ER alpha-mediated transcription as GW7604 and inhibit estradiol-induced proliferation of the MCF-7 cell line with a similar potency as GW7604. Unlike GW7604, neither analog has a significant effect on cellular ER alpha levels, suggesting that the carboxylate is a key determinant in GW7604 action and, for the first time, showing that this group is responsible for inducing ER alpha degradation in breast cancer cells.
用于乳腺癌治疗的抗雌激素药物可分为两类，它们对雌激素受体（ER）α稳定性的影响有所不同。选择性雌激素受体调节剂（SERM）可稳定ERα，而选择性雌激素受体下调剂（SERD）则会导致细胞内ERα水平降低。一种具有临床相关性的抗雌激素药物GW7604，尽管其与SERM 4-羟基他莫昔芬具有相同的分子骨架，但似乎是通过类似SERD的机制发挥作用。为了研究GW7604中负责SERD活性的潜在结构特征，采用一种新的改进合成路线合成了GW7604及其两种类似物，并测试了它们对ERα功能和细胞增殖的影响。这两种类似物分别用丙烯酰胺或甲基乙烯基酮取代了GW7604的丙烯酸基团，它们对ERα的结合亲和力低于GW7604，但与GW7604一样，对雌二醇诱导的ERα介导的转录激活具有类似的拮抗作用，并且以与GW7604相似的效力抑制雌二醇诱导的MCF-7细胞系增殖。与GW7604不同，这两种类似物对细胞内ERα水平均无显著影响，这表明羧酸盐是GW7604作用的关键决定因素，并且首次表明该基团负责诱导乳腺癌细胞中的ERα降解。
