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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Munuganti RS, Leblanc E, Axerio-Cilies P, Labriere C, Frewin K, Singh K, Hassona MD, Lack NA, Li H, Ban F, Tomlinson Guns E, Young R, Rennie PS, Cherkasov A

Targeting the binding function 3 (BF3) site of the androgen receptor through virtual screening. 2. development of 2-((2-phenoxyethyl) thio)-1H-benzimidazole derivatives.

J Med Chem. 2013 Feb 14;56(3):1136-48. doi: 10.1021/jm3015712. Epub 2013 Jan 18.

PubMed ID

23301637 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bicalutamide	Androgen receptor	IC 50 (nM)	>100000	N/A	N/A	Details
Enzalutamide	Androgen receptor	IC 50 (nM)	>100000	N/A	N/A	Details