Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer
作者:Yunlong Lu、Lauren M. Gutgesell、Rui Xiong、Jiong Zhao、Yangfeng Li、Carlo I. Rosales、Michael Hollas、Zhengnan Shen、Jesse Gordon-Blake、Katherine Dye、Yueting Wang、Sue Lee、Hu Chen、Donghong He、Oleksii Dubrovyskyii、Huiping Zhao、Fei Huang、Amy W. Lasek、Debra A. Tonetti、Gregory R. J. Thatcher
DOI:10.1021/acs.jmedchem.9b01580
日期:2019.12.26
The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because
临床甾体选择性雌激素受体 (ER) 降解剂 (SERD) 氟维司群对转移性乳腺癌有效,但药代动力学不佳,促使开发口服生物可利用的非甾体 SERD,目前正在临床试验中。这些试验针对局部乳腺癌以及外周转移,但由于缺乏血脑屏障渗透,脑转移患者通常被排除在外。合成了一个具有碱性氨基侧臂的苯并噻吩 SERDs (B-SERDs) 的新家族。ERα 的蛋白酶体降解是由 B-SERD 诱导的,它实现了口服和脑生物利用度的目标,同时保持了与 ERα 的高亲和力结合,并且在对内分泌治疗有抵抗力或携带 ESR1 突变的细胞系中,效力和功效与氟维司群相当。