Abstract 1727: DNA-binding domain as an alternative target site on androgen receptor for prostate cancer therapy: Pre-clinical in vivo study of a novel small molecule for drug development
Authors: Hassona Mohamed DH , Chan Leslie G. , Meckling Gray R. , Li Huifang , LeBlanc Eric , Ban Fuqiang , Cherkasov Artem , Rennie Paul S. , Guns Emma 
Published: August 2015

Androgen receptor (AR) is a key regulatory transcription factor in the development of prostate cancer (PCa). Common treatments for PCa include hormone therapy, radiotherapy and surgery. However, many PCa patients develop resistance towards hormone therapies in later stages of PCa. There is growing evidence suggesting that AR splice variants render PCa treatments that target the LBD, such as enzalutimide, ineffective. Our objective is to develop a drug to treat recurrent and metastatic PCa by targeting the DNA Binding Domain (DBD). Through in silico docking prediction and in vitro bioassays, we have identified a novel small molecule - VPC-14449 (4-(4-(4,5-bromo-1H-imidazol-1-yl)thiazol-2-yl)morpholine) - that may inhibit AR activation through targeting DBD. In order to bring VPC -14449 into the clinic, we conducted preclinical in vivo studies to determine both toxicity and efficacy.

CD1 mice were treated with 25, 50, and 100 mg/kg of VPC-14449 I.P. twice daily for four weeks to determine the maximum tolerable dose. During this time, we assessed the signs of physical toxicity, behavioral changes, and gross manifestations of stress. At the end of the experiment, the mice were euthanized and organs were collected for further immunohistochemical analysis. Furthermore, we assessed the in vivo therapeutic effects of VPC-14449 in different nude mouse xenograft models including LNCaP, MR49-F, and C4-2. Body weight, tumor volume (π/6 x length x width x height) and PSA were measured weekly. LNCaP xenograft mice were castrated when PSA level reached 25 ng/ml. Mice were randomly assigned to one of the three treatment groups (VPC-14449 (100mg/kg), enzalutimide (10 mg/kg), or vehicle) when PSA level returned to 25 ng/ml (for LNCaP xenografts) or when the tumor sizes reached 100mm3(for MR49-F and C4-2 xenografts). The mice were treated I.P. twice daily for four weeks before euthanization.

Toxicity studies revealed no signs of physical toxicity, behavioral changes, and gross manifestations of stress in animals treated with up to 100 mg/kg dose of VPC-14449. Efficacy studies revealed that VPC-14449 effectively suppresses tumor growth in LNCaP, MR49 and C4-2 xenografts with P value &lt;0.01, &lt;0.05 and &lt; 0.001 respectively, when compared to control. VPC-14449 also significantly reduced PSA levels in LNCaP xenografts (p value &lt;0.01). The results suggest that VPC-14449 is effectively suppressing PCa tumor growth even in androgen insensitive and MDV resistant PCa cell lines in vivo.

Citation Format: Mohamed DH Hassona, Leslie G. Chan, Gray R. Meckling, Huifang Li, Eric LeBlanc, Fuqiang Ban, Artem Cherkasov, Paul S. Rennie, Emma Guns. DNA-binding domain as an alternative target site on androgen receptor for prostate cancer therapy: Pre-clinical in vivo study of a novel small molecule for drug development. [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 1727. doi:10.1158/1538-7445.AM2015-1727