雄激素受体
前列腺癌
转录因子
癌症研究
小分子
雄激素
虚拟筛选
化学
细胞生物学
生物
癌症
基因
药物发现
激素
内分泌学
生物信息学
生物化学
遗传学
作者
Kush Dalal,Fuqiang Ban,Huifang Li,Hélène Morin,Mani Roshan-Moniri,Kevin J. Tam,Ashley Shepherd,Aishwariya Sharma,James W. Peacock,Michael Carlson,Eric Leblanc,Carl Perez,Franck Duong,Christopher J. Ong,Paul S. Rennie,Artem Cherkasov
标识
DOI:10.1016/j.canlet.2018.08.016
摘要
Prostate cancer (PCa) is a leading cause of death for men in North America. The androgen receptor (AR) - a hormone inducible transcription factor - drives expression of tumor promoting genes and represents an important therapeutic target in PCa. The AR is activated by steroid recruitment to its ligand binding domain (LBD), followed by receptor nuclear translocation and dimerization via the DNA binding domain (DBD). Clinically used small molecules interfere with steroid recruitment and prevent AR-driven tumor growth, but are rendered ineffective by emergence of LBD mutations or expression of constitutively active variants, such as ARV7, that lack the LBD. Both drug-resistance mechanisms confound treatment of this 'castration resistant' stage of PCa (CRPC), characterized by return of AR signalling. Here, we employ computer-aided drug-design to develop small molecules that block the AR-DBD dimerization interface, an attractive target given its role in AR activation and independence from the LBD. Virtual screening on the AR-DBD structure led to development of prototypical compounds that block AR dimerization, inhibiting AR-transcriptional activity through a LBD-independent mechanism. Such inhibitors may potentially circumvent AR-dependent resistance mechanisms and directly target CRPC tumor growth.
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