2. Academic Validation
  3. Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927

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

Affiliation

  • 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.

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