%0 Journal Article
%T Maximizing ER-¦Á Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927
%J -
%D 2019
%R https://doi.org/10.1021/acsmedchemlett.8b00414
%X The further optimization of ER-¦Á 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-¦Á degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-¦Á levels. However, despite superior oral exposure, 5a (ER-¦Á degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-¦Á 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
%U https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00414