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.

Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer

“…Recently, using our established in silico drug design approach (13,23,24), we discovered a surface-exposed region on the AR-DBD, including residues Ser-579 to Lys-610, which was established to be targetable by small molecule inhibitors to potentially inhibit the AR by interfering with DNA binding. Computer-aided high throughput screening identified candidate molecules that were effective for abolishing AR transcriptional activity in LNCaP cells and displayed no interference or binding with the AR-LBD (25).…”

Androgen receptor antagonists for prostate cancer therapy

“…Several structural scaffolds have been identified through virtual screening as binders to this BF3 region and were confirmed to have antagonistic effects not only on AR transcriptional activity (Lack et al 2011), but also on proliferation of LNCaP and enz-resistant cells (Munuganti et al 2013).…”

Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif

“…Interaction of peptides with BF-3 has been difficult to demonstrate, but more recently a group of ligand derivatives of 2-((2-phenoxyethyl)thio)-1H-benzimidazole was shown to bind specifically to the BF-3 pocket of the AR (38,48). One of these ligands is 2-((2-(2,6-dimethylphenoxy)ethyl)thio)-1H-benzo[d]imidazole (compound 49 (CPD49); Fig.…”

“…One of these ligands is 2-((2-(2,6-dimethylphenoxy)ethyl)thio)-1H-benzo[d]imidazole (compound 49 (CPD49); Fig. 6A), which exerts significant anti-androgen potency in LNCaP and enzalutamide-resistant prostate cancer cell lines (38,48). We therefore used this ligand to determine whether it would compete with the GARRPR peptides for binding to the BF-3 pocket.…”

“…imidazole was synthesized in house essentially as described (38) with minor modifications in the addition of 1H-benzimidazole-2-thiol to 2-(2-bromoethoxy)-1,3-dimethylbenzene in the presence of potassium iodide and carbonate. The latter reactant was synthesized by allowing 1,2-dibromoethane to react with a commercially available 2,6-dimethylphenol in the presence of potassium carbonate as a base at 60°C, as described previously (39).…”