"True" Antiandrogens-Selective Non-Ligand-Binding Pocket Disruptors of Androgen Receptor-Coactivator Interactions: Novel Tools for Prostate Cancer

被引:49
作者
Caboni, Laura [1 ]
Kinsella, Gemma K. [1 ]
Blanco, Fernando [1 ]
Fayne, Darren [1 ]
Jagoe, William N. [1 ]
Carr, Miriam [1 ]
Williams, D. Clive
Meegan, Mary J. [2 ]
Lloyd, David G. [1 ]
机构
[1] Trinity Coll Dublin, Mol Design Grp, Sch Biochem & Immunol, Trinity Biomed Sci Inst, Dublin 2, Ireland
[2] Trinity Coll Dublin, Sch Pharm & Pharmaceut Sci, Trinity Biomed Sci Inst, Dublin 2, Ireland
关键词
CARCINOMA-CELL-LINE; BIOLOGICAL EVALUATION; ESTROGEN-RECEPTOR; IN-VITRO; INHIBITION; MIFEPRISTONE; RECOGNITION; SUPERFAMILY; MUTATION; THERAPY;
D O I
10.1021/jm201438f
中图分类号
R914 [药物化学];
学科分类号
100705 [微生物与生化药学];
摘要
Prostate cancer (PCa) therapy typically involves administration of "classical" antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the figand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and figand-based virtual screening. Compounds demonstrate full ("true") antagonism in AR with low micromolar potency, selectivity over estrogen receptors alpha and beta and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.
引用
收藏
页码:1635 / 1644
页数:10
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