| Literature DB >> 32551022 |
Jun Liang1, Robert Blake1, Jae Chang1, Lori S Friedman1, Simon Goodacre2, Steven Hartman1, Ellen Rei Ingalla1, James R Kiefer1, Tracy Kleinheinz1, Sharada Labadie1, Jun Li1, Kwong Wah Lai3, Jiangpeng Liao3, Vidhi Mody1, Neville McLean2, Ciara Metcalfe1, Michelle Nannini1, Daniel Otwine1, Yingqing Ran1, Nick Ray2, Fabien Roussel2, Amy Sambrone1, Deepak Sampath1, Maia Vinogradova1, John Wai3, Tao Wang3, Kuen Yeap2, Amy Young1, Jason Zbieg1, Birong Zhang1, Xiaoping Zheng3, Yu Zhong1, Xiaojing Wang1.
Abstract
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of 6 that showed ionic interaction of azetidine with Asp351 residue. Importantly, 12 showed favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.Entities:
Year: 2020 PMID： 32551022 PMCID： PMC7294714 DOI： 10.1021/acsmedchemlett.0c00224
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345