Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer
Abstract
Interest in developing androgen receptor (AR) inhibitors with novel mechanism of action is slowly increasing since commercial anti-androgens (Bicalutamide, Flutamide, Nilutamide and Enzalutamide) face therapeutic limitations. Current therapies fail over a period of time because they all target hormone binding pocket on AR to which the receptor has already developed effective resistance mechanisms. One of the promising strategies to combat drug resistance is to develop the inhibitors that target an alternative binding pocket of the AR, called Binding Function 3 (BF3). In the current study, we report indole chemical series, identified through systematic in silico screen, as leading AR BF3 inhibitors. The most potent inhibitor (compound VPC-13566) demonstrated excellent anti-androgen potency, anti-PSA activity and abrogates androgen-induced proliferation of LNCaP and Enzalutamide-resistant prostate cancer cell lines. Moreover, it reduces the expression of AR dependant genes more effectively than current gold-standard Enzalutamide. These findings provide evidence that targeting AR BF3 pocket using small molecule inhibitors is a viable therapeutic approach for patients with advanced prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA596651
Entities
People
- Artem Cherkasov
- Betty Diamond
- Paul Rennie
Organizations
- University of British Columbia