Targeting the Binding Function 3 (BF3) Site of the Androgen Receptor Through Virtual Screening. 2. Development of 2‑((2-phenoxyethyl) thio)‑1H‑benzimidazole Derivatives
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...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-02, Vol.56 (3), p.1136-1148 |
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| creator | Munuganti, Ravi Shashi Nayana Leblanc, Eric Axerio-Cilies, Peter Labriere, Christophe Frewin, Kate Singh, Kriti Hassona, Mohamed D. H Lack, Nathan A Li, Huifang Ban, Fuqiang Tomlinson Guns, Emma Young, Robert Rennie, Paul S Cherkasov, Artem |
| description | 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. 2011. 54, 8563 ). In the current study, based on the prior results, we have developed structure–activity 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. |
| doi_str_mv | 10.1021/jm3015712 |
| format | Article |
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| subjects | Benzimidazoles - chemistry Benzimidazoles - metabolism Binding Sites Cell Line, Tumor Crystallography, X-Ray Humans Male Molecular Structure Prostate-Specific Antigen - metabolism Receptors, Androgen - metabolism |
| title | 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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