Characterization of a new class of androgen receptor antagonists with potential therapeutic application in advanced prostate cancer
Li H, Hassona MD, Lack NA, Axerio-Cilies P, Leblanc E, Kanaan N, Frewin K, Singh K, Adomat H, Bohm KJ, Prinz H, Guns ET, Rennie PS, Cherkasov A. Mol Cancer Ther. 2013 Aug 12. [Epub ahead of print]


1Vancouver Prostate Centre, Vancouver Prostate Centre, University of British Columbia.


The human androgen receptor (AR) plays a major role in the development and progression of prostate cancer (PCa) and represents a well-established drug target. All clinically approved AR antagonists possess similar chemical structures and exhibit the same mode of action on the AR. While initially effective, resistance to these AR antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the AR is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of AR antagonists that could help overcome the problem of resistance. In this study, we implemented and utilized the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit AR transcriptional activity, but also induce almost complete degradation of the AR. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that demonstrated strong androgen displacement potency, effectively inhibited AR transcriptional activity, and possesses a profound ability to cause degradation of AR. Notably, VPC-3033 exhibited significant activity against PCa cells that have already developed resistance to the second-generation antiandrogen Enzalutamide (formerly known as MDV3100). VPC-3033 also demonstrated strong anti-AR activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists that can help address the problem of antiandrogen resistance in PCa.