Identification of Novel Androgen Receptor Antagonists Using Structure- and Ligand-Based Methods

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). The AR hormone-binding site (HBS) is intensively studied and represents the target area for current antiandrogens including Bicalutamide and structurally related Enzalutamide. As resistance to antiandrogens invariably emerges in advanced prostate cancer, there exists a high medical need for the identification and development of novel AR antagonists of different chemotypes. Given the wealth of structural information on the AR in complex with a variety of ligands, we have applied an integrated structure- and ligand-based virtual screening methodology to identify novel AR antagonists. Virtual hits generated by a consensus voting approach were experimentally evaluated and resulted in the discovery of a number of structurally diverse submicromolar antagonists of the AR. In particular, one identified compound demonstrated anti-AR potency <i>in vitro</i> that is comparable to the clinically used Bicalutamide. These results set a ground for the development of novel classes of PCa drugs that are structurally different from current AR antagonists

Discovery of 1<i>H</i>‑Indole-2-carboxamides as Novel Inhibitors of the Androgen Receptor Binding Function 3 (BF3)

To overcome resistance to conventional anti-androgens of human androgen receptor (AR), the allosteric site of the AR binding function 3 (BF3) was investigated as an alternative target for small molecule therapeutics. A library of 1<i>H-</i>indole-2-carboxamides were discovered as BF3 inhibitors and exhibited strong antiproliferative activity against LNCaP and enzalutamide-resistant prostate cancer cell lines. Several of the lead compounds may prove of particular benefit as a novel alternative treatment for castration-resistant prostate cancers

Discovery of Small-Molecule Inhibitors Selectively Targeting the DNA-Binding Domain of the Human Androgen Receptor

The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (<b>1</b>), a structural analogue (<b>6</b>) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (<b>25</b>) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7

Discovery of Small-Molecule Inhibitors Selectively Targeting the DNA-Binding Domain of the Human Androgen Receptor

The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (<b>1</b>), a structural analogue (<b>6</b>) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (<b>25</b>) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7

Targeting the Binding Function 3 (BF3) Site of the Androgen Receptor Through Virtual Screening. 2. Development of 2‑((2-phenoxyethyl) thio)‑1<i>H</i>‑benzimidazole Derivatives

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)-1<i>H</i>-benzimidazole and 2-((2-phenoxyethyl)­thio)-1<i>H</i>-indole as lead BF3 inhibitors. Some of the developed BF3 ligands demonstrated significant antiandrogen potency against LNCaP and Enzalutamide-resistant prostate cancer cell lines

Targeting the Binding Function 3 (BF3) Site of the Androgen Receptor Through Virtual Screening. 2. Development of 2‑((2-phenoxyethyl) thio)‑1<i>H</i>‑benzimidazole Derivatives

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)-1<i>H</i>-benzimidazole and 2-((2-phenoxyethyl)­thio)-1<i>H</i>-indole as lead BF3 inhibitors. Some of the developed BF3 ligands demonstrated significant antiandrogen potency against LNCaP and Enzalutamide-resistant prostate cancer cell lines