Burks Heather E, Abrams Tinya, Kirby Christina A, Baird Jason, Fekete Alexander, Hamann Lawrence G, Kim Sunkyu, Lombardo Franco, Loo Alice, Lubicka Danuta, Macchi Kaitlin, McDonnell Donald P, Mishina Yuji, Norris John D, Nunez Jill, Saran Chitra, Sun Yingchuan, Thomsen Noel M, Wang Chunrong, Wang Jianling, Peukert Stefan
Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham, North Carolina 27710, United States.
J Med Chem. 2017 Apr 13;60(7):2790-2818. doi: 10.1021/acs.jmedchem.6b01468. Epub 2017 Mar 15.
Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
四氢异喹啉40已被鉴定为一种强效的雌激素受体α拮抗剂和选择性雌激素受体降解剂（SERD），在体内表现出良好的口服生物利用度、抗肿瘤功效和SERD活性。我们概述了导致四氢异喹啉40的四氢异喹啉支架的发现和化学优化过程，并展示了该支架的外消旋化、临床前物种的药代动力学研究以及四氢异喹啉40在MCF-7人乳腺癌异种移植模型中的体内疗效。
