| Literature DB >> 34251202 |
Jun Liang1, Jason R Zbieg1, Robert A Blake1, Jae H Chang1, Stephen Daly2, Antonio G DiPasquale1, Lori S Friedman1, Thomas Gelzleichter1, Matthew Gill2, Jennifer M Giltnane1, Simon Goodacre2, Jane Guan1, Steven J Hartman1, Ellen Rei Ingalla1, Lorn Kategaya1, James R Kiefer1, Tracy Kleinheinz1, Sharada S Labadie1, Tommy Lai3, Jun Li1, Jiangpeng Liao3, Zhiguo Liu3, Vidhi Mody1, Neville McLean2, Ciara Metcalfe1, Michelle A Nannini1, Jason Oeh1, Martin G O'Rourke2, Daniel F Ortwine1, Yingqing Ran1, Nicholas C Ray2, Fabien Roussel2, Amy Sambrone1, Deepak Sampath1, Leah K Schutt1, Maia Vinogradova1, John Wai3, Tao Wang3, Ingrid E Wertz1, Jonathan R White2, Siew Kuen Yeap2, Amy Young1, Birong Zhang1, Xiaoping Zheng3, Wei Zhou1, Yu Zhong1, Xiaojing Wang1.
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.Entities:
Year: 2021 PMID： 34251202 DOI： 10.1021/acs.jmedchem.1c00847
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446