Targeting the Binding Function 3 (BF3) Site of the Androgen Receptor Through Virtual Screening. 2. Development of 2-((2-phenoxyethyl) thio)-1H-benzimidazole Derivatives

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• 作者：Ravi Shashi Nayana Munuganti ; Eric Leblanc ; Peter Axerio-Cilies ; Christophe Labriere ; Kate Frewin ; Kriti Singh ; Mohamed D. H. Hassona ; Nathan A. Lack ; Huifang Li ; Fuqiang Ban ; Emma Tomlinson Guns ; Robert Young ; Paul S. Rennie ; Artem Cherkasov
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1136-1148
• 全文大小：559K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

The human androgen receptor (AR) is a proven therapeutic target in prostate cancer. All current antiandrogens, such as Bicalutamide, Flutamide, Nilutamide, and Enzalutamide, target the buried hydrophobic androgen binding pocket of this protein. However, effective resistance mechanisms against these therapeutics exist such as mutations occurring at the target site. To overcome these limitations, the surface pocket of the AR called binding function 3 (BF3) was characterized as an alternative target for small molecule therapeutics. A number of AR inhibitors directly targeting the BF3 were previously identified by us ( J. Med. Chem.<span class="NLM_x"> span>2011. 54<span class="NLM_x">, span>8563). In the current study, based on the prior results, we have developed structure鈥揳ctivity relationships that allowed designing a series of 2-((2-phenoxyethyl)thio)-1H-benzimidazole and 2-((2-phenoxyethyl)thio)-1H-indole as lead BF3 inhibitors. Some of the developed BF3 ligands demonstrated significant antiandrogen potency against LNCaP and Enzalutamide-resistant prostate cancer cell lines.