A novel steroidal antiandrogen targeting wild type and mutant androgen receptors.

Prostate cancer (PCa) progression is enhanced by androgen and treatment with antiandrogens represents an alternative to castration. While patients initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years by expressing androgen receptor (AR) mutants. Such mutations, indeed, promote unfavorable agonistic behavior from classical antagonists. Here, we have synthesized and screened 37 novel compounds derived from dihydrotestosterone (DHT), cyanolutamide and hydroxyflutamide. These derivatives were tested for their potential antagonistic activity using a luciferase reporter gene assay and binding properties were determined for wild type (WT) and mutant ARs (T877A, W741C, W741L, H874Y). In the absence and presence of antiandrogens, androgen dependent cellular proliferation and prostate specific antigen (PSA) expression were assayed in the prostate cancer cell line LNCaP by crystal violet, real time PCR and by Western blots. Also, cellular proliferation and PSA expression were assayed in 22Rv1. A novel compound RB346, derived from DHT, was found to be an antagonist for all tested AR forms, preventing DHT induced proliferation and PSA expression in LNCaP and 22Rv1 cells. RB346 displayed no agonistic activity, in contrast to the non-steroidal antiandrogen bicalutamide (Casodex) with unfavorable agonistic activity for W741L-AR. Additionally, RB346 has a slightly higher binding affinity for WT-AR, T877A-AR and H874Y-AR than bicalutamide. Thus, RB346 is the first potent steroidal antiandrogen with efficacy for WT and various AR mutants.

Andrieu T ，Bertolini R ，Nichols SE ，Setoud R ，Frey FJ ，Baker ME ，Frey BM ... -  《-》

Suppression of mutant androgen receptors by flutamide.

Ishioka J ，Hara S ，Isaacs JT ，Tomura A ，Nishikawa K ，Kageyama Y ... -  《-》

Study of the impact of the T877A mutation on ligand-induced helix-12 positioning of the androgen receptor resulted in design and synthesis of novel antiandrogens.

Zhou J ，Liu B ，Geng G ，Wu JH ... -  《-》

Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome.

Hara T ，Miyazaki J ，Araki H ，Yamaoka M ，Kanzaki N ，Kusaka M ，Miyamoto M ... -  《CANCER RESEARCH》

Effects of steroidal and non-steroidal antiandrogens on wild-type and mutant androgen receptors.

Molecular basis for secondary antiandrogen therapy in prostate cancer with mutant androgen receptors (ARs) is not fully elucidated. Effects of steroidal and non-steroidal antiandrogens on transcriptional activities of wild-type and mutant (W741C, T877A, and W741C+T877A) ARs were measured. Crystal structure analysis and docking studies were performed using Molecular Operating Environment (MOE) package. DHT-induced transcriptional activity of the T877A mutant and the W741C mutant was suppressed by bicalutamide and hydroxyflutamide, respectively. Nilutamide suppressed the W741C mutant and the double mutant. Cyproterone acetate modestly inhibited the W741C mutant and the double mutant. The structural studies suggested that nilutamide and cyproterone acetate retain their antiandrogenic properties against both the W741C mutant and the double mutant due to fact that mutation W741C does not permit formation of key hydrophobic interaction between ligand and AR ligand binding domain, which is necessary for their conversion into agonists. Switching antiandrogens may be reasonable in prostate cancer with mutant ARs.

Urushibara M ，Ishioka J ，Hyochi N ，Kihara K ，Hara S ，Singh P ，Isaacs JT ，Kageyama Y ... -  《-》