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Estrogen plays multiple roles in health and disease, exerting its effects through the classical estrogen receptors (ERα and ERβ) and the G protein‑coupled estrogen receptor (GPER). Current ER‑targeting ligands, including the therapeutic ERα antagonist tamoxifen, have been shown to cross‑activate GPER. This cross‑activation is hypothesized to contribute to clinically observed endocrine resistance in breast cancer, highlighting the potential benefit of truly ER‑selective antagonists. We report the identification of a novel class of ER‑selective ligands that lack cross‑reactivity towards GPER, identifying a truly ER‑selective agonist (AB‑1) and antagonist (AB‑82P). Importantly, AB‑82P degrades a clinically relevant ERα mutant and exhibits inhibitory effects in cellular models of endocrine resistance. This novel class of ER‑selective ligands can aid in improving our understanding of the individual estrogen receptors in estrogen biology and more importantly, provide a structural basis for the development of new, truly ER‑selective antagonists for the treatment of ERα‑positive breast cancers.