Identification of Oral Bioavailable Coumarin Derivatives as Potential AR Antagonists Targeting Prostate Cancer

Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative <b>1</b>, which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound <b>4a</b> (IC₅₀ = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC₅₀ = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, <b>4a</b> showed superior efficacy against AR^F876L/T877A and AR^W741C mutants compared to darolutamide and enzalutamide. Moreover, <b>4a</b> exhibited favorable pharmacokinetic profiles (<i>F</i> = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of <b>4a</b> as a promising oral AR antagonist for overcoming drug resistance in PCa.