Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927

  • ACS Med Chem Lett. 2018 Dec 6;10(1):50-55. doi: 10.1021/acsmedchemlett.8b00414.
Mehmet Kahraman  1 ,  Steven P Govek  1 ,  Johnny Y Nagasawa  1 ,  Andiliy Lai  1 ,  Celine Bonnefous  1 ,  Karensa Douglas  1 ,  John Sensintaffar  1 ,  Nhin Liu  1 ,  KyoungJin Lee  1 ,  Anna Aparicio  1 ,  Josh Kaufman  1 ,  Jing Qian  1 ,  Gang Shao  1 ,  Rene Prudente  1 ,  James D Joseph  1 ,  Beatrice Darimont  1 ,  Daniel Brigham  1 ,  Richard Heyman  1 ,  Peter J Rix  1 ,  Jeffrey H Hager  1 ,  Nicholas D Smith  1
Affiliations
  • 1. Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
PMID: 30655946 DOI: 10.1021/acsmedchemlett.8b00414
Abstract

The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective Estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast Cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast Cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast Cancer.