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.
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.
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada.
authors.forename: Ravi Shashi Nayana
authors.initials: RS
authors.lastname: Munuganti
authors.forename: Eric
authors.initials: E
authors.lastname: Leblanc
authors.forename: Peter
authors.initials: P
authors.lastname: Axerio-Cilies
authors.forename: Christophe
authors.initials: C
authors.lastname: Labriere
authors.forename: Kate
authors.initials: K
authors.lastname: Frewin
authors.forename: Kriti
authors.initials: K
authors.lastname: Singh
authors.forename: Mohamed D H
authors.initials: MD
authors.lastname: Hassona
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Lack
authors.forename: Huifang
authors.initials: H
authors.lastname: Li
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Ban
authors.forename: Emma
authors.initials: E
authors.lastname: Tomlinson Guns
authors.forename: Robert
authors.initials: R
authors.lastname: Young
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D015394:Molecular Structure; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen