Discovery of a Novel Androgen Receptor Antagonist Manifesting Evidence to Disrupt the Dimerization of the Ligand-Binding Domain via Attenuating the Hydrogen-Bonding Network Between the Two Monomers

• Published in: Journal of medicinal chemistry 2021-12, Vol.64 (23), p.17221-17238
• Main Authors: Fu, Weitao, Zhang, Minkui, Liao, Jianing, Tang, Qing, Lei, Yixuan, Gong, Zhou, Shan, Luhu, Duan, Mojie, Chai, Xin, Pang, Jinping, Tang, Chun, Wang, Xuwen, Xu, Xiaohong, Li, Dan, Sheng, Rong, Hou, Tingjun
• Format: Article
• Language: English
• Subjects: Androgen Receptor Antagonists - chemistry; Androgen Receptor Antagonists - pharmacology; Binding Sites; Cell Line; Dimerization; Drug Discovery; Humans; Hydrogen Bonding; Ligands; Molecular Dynamics Simulation; Receptors, Androgen - metabolism; Transcription, Genetic - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01287

Androgen receptor (AR) has proved to be a vital drug target for treating prostate cancer. Here, we reported the discovery of a novel AR antagonist 92 targeting the AR ligand-binding pocket, but distinct from the marketed drug enzalutamide (Enz), 92 demonstrated inhibition on the AR ligand-binding domain (LBD) dimerization, which is a novel mechanism reported for the first time. First, a novel hit (26, IC50 = 5.57 μM) was identified through virtual screening based on a theoretical AR LBD dimer bound with the Enz model. Then, guided by molecular modeling, 92 was discovered with 32.7-fold improved AR antagonistic activity (IC50 = 0.17 μM). Besides showing high bioactivity and safety, 92 can inhibit AR nuclear translocation. Furthermore, 92 inhibited the formation of the AR LBD dimer, possibly through attenuating the hydrogen-bonding network between the two monomers. This interesting finding would pave the way for the discovery of a new class of AR antagonists.