کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8956111 | 1646136 | 2018 | 31 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer
ترجمه فارسی عنوان
انتخابی هدفمند سازی رابط دیمریزاسیون گیرنده آندروژن انسان با مولکول های کوچک برای درمان سرطان پروستات مقاوم به کاستاریکا
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کلمات کلیدی
گیرنده آندروژن، سرطان پروستات، اندازه گیری مهار کننده مولکول کوچک،
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 437, 28 November 2018, Pages 35-43
Journal: Cancer Letters - Volume 437, 28 November 2018, Pages 35-43
نویسندگان
Kush Dalal, Fuqiang Ban, Huifang Li, Hélène Morin, Mani Roshan-Moniri, Kevin J. Tam, Ashley Shepherd, Aishwariya Sharma, James Peacock, Michael L. Carlson, Eric LeBlanc, Carl Perez, Franck Duong, Christopher J. Ong, Paul S. Rennie, Artem Cherkasov,