title: Identification of a potent antiandrogen that targets the BF3 site of the androgen receptor and inhibits enzalutamide-resistant prostate cancer.
abstract: There has been a resurgence of interest in the development of androgen receptor (AR) inhibitors with alternative modes of action to overcome the development of resistance to current therapies. We demonstrated previously that one promising strategy for combatting mutation-driven drug resistance is to target the Binding Function 3 (BF3) pocket of the receptor. Here we report the development of a potent BF3 inhibitor, 3-(2,3-dihydro-1H-indol-2-yl)-1H-indole, which demonstrates excellent antiandrogen potency and anti-PSA activity and abrogates the androgen-induced proliferation of androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines. Moreover, this compound effectively reduces the expression of AR-dependent genes in PCa cells and effectively inhibits tumor growth in vivo in both LNCaP and MR49F xenograft models. These findings provide evidence that targeting the AR BF3 pocket represents a viable therapeutic approach to treat patients with advanced and/or resistant prostate cancer.
authors.forename: Ravi S N
authors.initials: RS
authors.lastname: Munuganti
authors.forename: Mohamed D H
authors.initials: MD
authors.lastname: Hassona
authors.forename: Eric
authors.initials: E
authors.lastname: Leblanc
authors.forename: Kate
authors.initials: K
authors.lastname: Frewin
authors.forename: Kriti
authors.initials: K
authors.lastname: Singh
authors.forename: Dennis
authors.initials: D
authors.lastname: Ma
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Ban
authors.forename: Michael
authors.initials: M
authors.lastname: Hsing
authors.forename: Hans
authors.initials: H
authors.lastname: Adomat
authors.forename: Nada
authors.initials: N
authors.lastname: Lallous
authors.forename: Christophe
authors.initials: C
authors.lastname: Andre
authors.forename: Jon Paul Selvam
authors.initials: JP
authors.lastname: Jonadass
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Emma Tomlinson
authors.initials: ET
authors.lastname: Guns
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C000599893:3-(2,3-dihydro-1H-indol-2-yl)-1H-indole; D000726:Androgen Antagonists; D001549:Benzamides; D007211:Indoles; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide