GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer

  • J Med Chem. 2021 Aug 26;64(16):11841-11856. doi: 10.1021/acs.jmedchem.1c00847.
Jun Liang  1 ,  Jason R Zbieg  1 ,  Robert A Blake  1 ,  Jae H Chang  1 ,  Stephen Daly  2 ,  Antonio G DiPasquale  1 ,  Lori S Friedman  1 ,  Thomas Gelzleichter  1 ,  Matthew Gill  2 ,  Jennifer M Giltnane  1 ,  Simon Goodacre  2 ,  Jane Guan  1 ,  Steven J Hartman  1 ,  Ellen Rei Ingalla  1 ,  Lorn Kategaya  1 ,  James R Kiefer  1 ,  Tracy Kleinheinz  1 ,  Sharada S Labadie  1 ,  Tommy Lai  3 ,  Jun Li  1 ,  Jiangpeng Liao  3 ,  Zhiguo Liu  3 ,  Vidhi Mody  1 ,  Neville McLean  2 ,  Ciara Metcalfe  1 ,  Michelle A Nannini  1 ,  Jason Oeh  1 ,  Martin G O'Rourke  2 ,  Daniel F Ortwine  1 ,  Yingqing Ran  1 ,  Nicholas C Ray  2 ,  Fabien Roussel  2 ,  Amy Sambrone  1 ,  Deepak Sampath  1 ,  Leah K Schutt  1 ,  Maia Vinogradova  1 ,  John Wai  3 ,  Tao Wang  3 ,  Ingrid E Wertz  1 ,  Jonathan R White  2 ,  Siew Kuen Yeap  2 ,  Amy Young  1 ,  Birong Zhang  1 ,  Xiaoping Zheng  3 ,  Wei Zhou  1 ,  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: 34251202 DOI: 10.1021/acs.jmedchem.1c00847
Abstract

Breast Cancer remains a leading cause of Cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective Estrogen receptor Degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.