4HLW

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

Summary for 4HLW

• Entry DOI: 10.2210/pdb4hlw/pdb
• Descriptor: Androgen receptor, TESTOSTERONE, 2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole, ... (6 entities in total)
• Functional Keywords: nuclear hormone receptor, androgen binding domain, transcriptional factor, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P10275
• Total number of polymer chains: 1
• Total formula weight: 30615.88

Authors

Ravi, S.N.M.,Leblanc, E.,Axerio-Cilies, P.,Labriere, C.,Frewin, K.,Hassona, M.D.H.,Lack, N.A.,Han, F.Q.,Guns, E.S.,Young, R.,Ban, F.,Rennie, P.S.,Cherkasov, A. (deposition date: 2012-10-17, release date: 2013-01-23, Last modification date: 2024-02-28)

Primary citation

Munuganti, R.S.,Leblanc, E.,Axerio-Cilies, P.,Labriere, C.,Frewin, K.,Singh, K.,Hassona, M.D.,Lack, N.A.,Li, H.,Ban, F.,Tomlinson Guns, E.,Young, R.,Rennie, P.S.,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., 56:1136-1148, 2013

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.

PubMed: 23301637
DOI: 10.1021/jm3015712

Experimental method

X-RAY DIFFRACTION (2.5 Å)