Characterization of molecular and structural determinants of selective estrogen receptor downregulators
Characterization of molecular and structural determinants of selective estrogen receptor downregulators
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DOI：
10.1007/s10549-006-9353-2
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发表时间：
2007-05-01
影响因子：
3.8
通讯作者：
Weatherman, Ross V.
中科院分区：
文献类型：
--
作者：
Fan, Meiyun;Rickert, Emily L.;Weatherman, Ross V.
用于乳腺癌治疗的抗雌激素可分为两类，它们对雌激素受体(ER)α稳定性的影响不同。选择性雌激素受体调节剂(SERM)稳定ERα，选择性雌激素受体下调调节剂(SERD)导致细胞ERα水平下降。一种临床相关的抗雌激素GW7604似乎通过SERD样机制发挥作用，尽管它与SERM 4-羟基他莫昔芬共享相同的分子支架。为了研究与SERD活性有关的GW7604的潜在结构特征，采用一种新的、改进的合成路线合成了GW7604和两个类似物，并测试了它们对ERα功能和细胞增殖的影响。这两个类似物以丙烯酰胺或甲基乙烯基酮取代GW7604的丙烯酸基团，对ERα的结合亲和力低于GW7604，但对雌激素诱导的ERα介导的转录激活的拮抗作用与GW7604相似，对雌激素诱导的MCF-7细胞株的增殖抑制作用与GW7604相似。与GW7604不同，这两种类似物对细胞ERα水平都没有显著影响，这表明羧酸盐是GW7604作用的关键决定因素，并首次表明这一组负责诱导乳腺癌细胞中ERα的降解。
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.