Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer

  • ACS Med Chem Lett. 2020 May 26;11(6):1342-1347. doi: 10.1021/acsmedchemlett.0c00224.
Jun Liang  1 ,  Robert Blake  1 ,  Jae Chang  1 ,  Lori S Friedman  1 ,  Simon Goodacre  2 ,  Steven Hartman  1 ,  Ellen Rei Ingalla  1 ,  James R Kiefer  1 ,  Tracy Kleinheinz  1 ,  Sharada Labadie  1 ,  Jun Li  1 ,  Kwong Wah Lai  3 ,  Jiangpeng Liao  3 ,  Vidhi Mody  1 ,  Neville McLean  2 ,  Ciara Metcalfe  1 ,  Michelle Nannini  1 ,  Daniel Otwine  1 ,  Yingqing Ran  1 ,  Nick Ray  2 ,  Fabien Roussel  2 ,  Amy Sambrone  1 ,  Deepak Sampath  1 ,  Maia Vinogradova  1 ,  John Wai  3 ,  Tao Wang  3 ,  Kuen Yeap  2 ,  Amy Young  1 ,  Jason Zbieg  1 ,  Birong Zhang  1 ,  Xiaoping Zheng  3 ,  Yu Zhong  1 ,  Xiaojing Wang  1
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Charles River Discovery Research Services UK Limited, 7-9 Spire Green Center, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
  • 3. WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
PMID: 32551022 DOI: 10.1021/acsmedchemlett.0c00224
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.

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