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 1, 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 4a (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, 4a showed superior efficacy
against ARF876L/T877A and ARW741C mutants compared
to darolutamide and enzalutamide. Moreover, 4a exhibited
favorable pharmacokinetic profiles (F = 66.24%) in
vivo and significant tumor growth inhibition in an LNCaP xenograft
mouse model upon oral administration. These results highlight the
potential of 4a as a promising oral AR antagonist for
overcoming drug resistance in PCa.