Identification\nof Oral Bioavailable Coumarin Derivatives\nas Potential AR Antagonists Targeting Prostate Cancer

Androgen receptor (AR) is a crucial driver of prostate\ncancer (PCa),\nbut acquired resistance to AR antagonists significantly undermines\ntheir clinical efficacy. We previously discovered coumarin derivative <b>1</b>, which is capable of disrupting AR ligand-binding domain\ndimers, offering the potential for overcoming resistance. However,\nits poor oral bioavailability limited further development. In this\nstudy, comprehensive structure optimizations led to compound <b>4a</b> (IC<sub>50</sub> = 0.051 μM), which exhibited comparable\nAR antagonistic activity to enzalutamide (IC<sub>50</sub> = 0.060\nμM) and demonstrated excellent selectivity over other nuclear\nreceptors in vitro. Especially, <b>4a</b> showed superior efficacy\nagainst AR<sup>F876L/T877A</sup> and AR<sup>W741C</sup> mutants compared\nto darolutamide and enzalutamide. Moreover, <b>4a</b> exhibited\nfavorable pharmacokinetic profiles (<i>F</i> = 66.24%) in\nvivo and significant tumor growth inhibition in an LNCaP xenograft\nmouse model upon oral administration. These results highlight the\npotential of <b>4a</b> as a promising oral AR antagonist for\novercoming drug resistance in PCa.