O'Dea Austin, Sondergard Chelsea, Sweeney Patrick, Arnatt Christopher Kent
Department of Chemistry, College of Arts and Sciences, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri United States.
ACS Med Chem Lett. 2018 Sep 4;9(9):901-906. doi: 10.1021/acsmedchemlett.8b00212. eCollection 2018 Sep 13.
The G protein-coupled estrogen receptor (GPER, GPR30) represents a promising target for the treatment of estrogen receptor α and β negative breast cancers. Previously reported agonists of GPER have shown that activation of GPER inhibits breast cancer cell proliferation. We report herein a new GPER agonist scaffold based upon in silico pharmacophore screening. Three of these compounds were found to increase cAMP at similar levels as the known GPER-selective agonist G-1. Compound was found to be selective for GPER (over estrogen receptor α and β) and inhibit breast cancer cell proliferation at levels consistent with G-1. Docking studies go on to suggest that both 5 and G-1 bind within the same binding pocket in GPER and point to possible key residues that are important in GPER activation.
G蛋白偶联雌激素受体（GPER，GPR30）是雌激素受体α和β阴性乳腺癌治疗的一个有前景的靶点。先前报道的GPER激动剂表明，GPER的激活可抑制乳腺癌细胞增殖。我们在此报告一种基于计算机辅助药效团筛选的新型GPER激动剂支架。发现其中三种化合物增加cAMP的水平与已知的GPER选择性激动剂G-1相似。发现化合物对GPER具有选择性（相对于雌激素受体α和β），并在与G-1一致的水平上抑制乳腺癌细胞增殖。对接研究进一步表明，5和G-1都结合在GPER的同一结合口袋内，并指出了在GPER激活中重要的可能关键残基。
