Abstract 3652: Development of novel chemical inhibitors targeting the N-terminal domain (NTD) of androgen receptor variants as anti-prostate cancer agents

Abstract

Abstract The androgen receptor (AR) signaling is a driver of prostate cancer. Current therapeutic strategy for advanced prostate cancer is to suppress the AR signaling by androgen deprivation therapy (ADT) via castration and by antiandrogens to stop androgens from working. However, prostate cancer cells are very versatile in circumventing the ADT and reactivate the AR via multiple mechanisms, resulting in lethal castration-resistant prostate cancer (CRPC). An alarming problem is the emergence of AR variants that lack the ligand-binding domain (such as AR-V7) in CRPC patients, which are constitutively active without the need for androgens. Studies revealed that AR-v7 expression level was correlated with the risk of tumor recurrence after radical prostatectomy and was associated with short patient survival. In addition, mutations in full-length AR is another important mechanism of aberrant AR activation in CRPC cells. Recently, it was found that the F876L mutation is sufficient to confer enzalutamide resistance in cell lines and xenograft model. The AR F876L mutant is detected in CRPC patients treated with an enzalutamide analogue (ARN-509). The AR W741C mutant was detected in CRPC patient treated with bicalutamide and was found to be paradoxically activated by bicalutamide. In this project, we propose to develop novel AR inhibitors that target the AR N-terminal domain (NTD). The rationale for this has at least three fold: i) All of the FDA-approved antiandrogens are targeting the AR-LBD and thereby all of them are inactive against AR-v7; ii) All of the known mechanisms that could account for AR reactivation in CRPC cells are critically depending on the AR-NTD to reactivate AR; and iii) Among the NTD, DNA-binding domain (DBD) and LBD domains, the NTD is the most different domain between the AR and other members of steroid receptors. By a panel of in vitro assays, we have discovered a series of compounds that target the AR-NTD and potently inhibit all forms of the AR variants in our assays, including AR-V7, the wild-type and multiple clinically-relevant mutants of full-length ARs. Our inhibitors showed selectivity towards AR as they are inactive against the close homology proteins within the same steroid family (such as GR and PR). This project could lead to novel AR-NTD inhibitors as drug candidates for treating CRPC patients who have acquired resistance to AR-LBD-directed therapies, such as enzalutamide and abiraterone. Citation Format: Jian Hui Wu. Development of novel chemical inhibitors targeting the N-terminal domain (NTD) of androgen receptor variants as anti-prostate cancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3652. doi:10.1158/1538-7445.AM2015-3652