雌激素受体鸟嘌呤腙共激活剂结合抑制剂的合成及生物学评价

Synthesis and biological evaluation of guanylhydrazone coactivator binding inhibitors for the estrogen receptor.

作者信息

LaFrate Andrew L, Gunther Jillian R, Carlson Kathryn E, Katzenellenbogen John A

机构信息

Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, USA.

出版信息

Bioorg Med Chem. 2008 Dec 1;16(23):10075-84. doi: 10.1016/j.bmc.2008.10.007. Epub 2008 Oct 7.

Most patients with hormone-responsive breast cancer eventually develop resistance to traditional antiestrogens such as tamoxifen, and this has become a major obstacle in their treatment. We prepared and characterized the activity of a series of 16 guanylhydrazone small molecules that are designed to block estrogen receptor (ER) activity through a non-traditional mechanism, by directly interfering with coactivator binding to agonist-liganded ER. The inhibitory activity of these compounds was determined in cell-based transcription assays using ER-responsive reporter gene and mammalian two-hybrid assays. Several of the compounds gave IC(50) values in the low micromolar range. Two secondary assays were used to confirm that these compounds were acting through the proposed non-traditional mode of estrogen inhibitory action and not as conventional antagonists at the ligand binding site.

大多数激素反应性乳腺癌患者最终会对他莫昔芬等传统抗雌激素药物产生耐药性，这已成为其治疗中的主要障碍。我们制备并表征了一系列16种胍腙小分子的活性，这些小分子旨在通过一种非传统机制阻断雌激素受体（ER）活性，即直接干扰共激活因子与激动剂配体化ER的结合。这些化合物的抑制活性在基于细胞的转录试验中通过ER反应性报告基因和哺乳动物双杂交试验来测定。其中几种化合物的IC（50）值在低微摩尔范围内。使用两种二级试验来确认这些化合物是通过所提出的非传统雌激素抑制作用模式起作用的，而不是作为配体结合位点的传统拮抗剂。