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

doi:10.1021/acs.jmedchem.1c01287

	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
	Fu, Weitao 1; Zhang, Minkui 1; Liao, Jianing 1; Tang, Qing 1; Lei, Yixuan 1; Gong, Zhou 2; Shan, Luhu 3; Duan, Mojie 4; Chai, Xin 1; Pang, Jinping 1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-12-09
卷号	64
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c01287
通讯作者	Li, Dan(lidancps@zju.edu.cn) ; Sheng, Rong(shengrong1973@163.com) ; Hou, Tingjun(tingjunhou@zju.edu.cn)
英文摘要	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 mu M) 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 mu M). 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.
资助项目	Key R&D Program of Zhejiang Province[2020C03010] ; National Natural Science Foundation of China[21575128] ; National Natural Science Foundation of China[81773632] ; Natural Science Foundation of Zhejiang Province[LZ19H300001]
WOS关键词	MOLECULAR-DYNAMICS ; PROSTATE-CANCER ; IDENTIFICATION ; ENZALUTAMIDE ; RESISTANCE ; MECHANISMS ; COUMARIN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000754727400016
资助机构	Key R&D Program of Zhejiang Province ; National Natural Science Foundation of China ; Natural Science Foundation of Zhejiang Province
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/127627]
专题	中国科学院合肥物质科学研究院
通讯作者	Li, Dan; Sheng, Rong; Hou, Tingjun
作者单位	1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China 2.Chinese Acad Sci, Innovat Acad Precis Measurement Sci & Technol, Natl Ctr Magnet Resonance Wuhan,State Key Lab Mag, Wuhan Inst Phys & Math,CAS Key Lab Magnet Resonan, Wuhan 430071, Hubei, Peoples R China 3.Univ Chinese Acad Sci, Zhejiang Canc Hosp, Inst Canc Res & Basic Med Sci, Canc Hosp,Chinese Acad Sci, Hangzhou 310022, Zhejiang, Peoples R China 4.Chinese Acad Sci, Natl Ctr Magnet Resonance Wuhan, Wuhan Inst Phys & Math, Key Lab Magnet Resonance Biol Syst,State Key Lab, Wuhan 430071, Hubei, Peoples R China 5.Peking Univ, Coll Chem & Mol Engn, Beijing Natl Lab Mol Sci, Beijing 100871, Peoples R China 6.Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China
推荐引用方式 GB/T 7714	Fu, Weitao,Zhang, Minkui,Liao, Jianing,et al. 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[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64.
APA	Fu, Weitao.,Zhang, Minkui.,Liao, Jianing.,Tang, Qing.,Lei, Yixuan.,...&Hou, Tingjun.(2021).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.JOURNAL OF MEDICINAL CHEMISTRY,64.
MLA	Fu, Weitao,et al."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".JOURNAL OF MEDICINAL CHEMISTRY 64(2021).