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

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

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.

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