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 M17-B15 was identified. M17-B15 showed strong in vitro efficacy against PCa but
had poor pharmacokinetic properties in vivo. In this
study, through rational design and structure–activity relationship
exploration, a series of thiadiazoleamide derivatives represented
by N29 (IC50 = 0.018 μM) were identified
with dominant AR antagonistic activity and remarkable anti-PCa activity in vitro. Furthermore, N29 effectively inhibited
a series of typical drug-resistant AR mutants. The improved oral bioavailability
of N29 facilitated its efficacy via oral
administration, significantly inhibiting LNCaP xenograft tumor in vivo, presenting a promising therapeutic application
for PCa.