Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer

About 75% of breast cancers are estrogen receptor alpha(ER-α) positive, and women typically initially respond well to antihormonal therapiessuch as tamoxifenand aromatase inhibitors, but resistance often emerges. Fulvestrantis a steroid-based, selective estrogen receptordegrader ( SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrantmust be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacyof a chromene series of ER modulators resulting in highly potent and efficacious SERDssuch as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy= 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy= 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacyin the MCF-7 cell line leads to compounds with r...