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

The further optimization of ER-α degradation efficacyof a series of ER modulators by refining side-chain substitution led to efficaciousselective estrogen receptordegraders ( SERDs). A fluoromethyl azetidinegroup 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 efficacyleads 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.