Discovery of Thiadiazoleamide Derivatives as Potent, Selective, and Orally Available Antagonists Disrupting Androgen Receptor Homodimer

Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist <b>M17-B15</b> was identified. <b>M17-B15</b> showed strong <i>in vitro</i> efficacy against PCa but had poor pharmacokinetic properties <i>in vivo</i>. In this study, through rational design and structure-activity relationship exploration, a series of thiadiazoleamide derivatives represented by <b>N29</b> (IC₅₀ = 0.018 μM) were identified with dominant AR antagonistic activity and remarkable anti-PCa activity <i>in vitro</i>. Furthermore, <b>N29</b> effectively inhibited a series of typical drug-resistant AR mutants. The improved oral bioavailability of <b>N29</b> facilitated its efficacy <i>via</i> oral administration, significantly inhibiting LNCaP xenograft tumor <i>in vivo</i>, presenting a promising therapeutic application for PCa.