Work

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

Year: 2024

Type: article

Abstract: 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 (IC 50 = 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.4c01464