Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer
Annual rept. 30 Sep 2013-29 Sep 2014
BRITISH COLUMBIA UNIV VANCOUVER
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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 demonstrated clear reduction of tumour growth in tumor xenograft models in mice. Based on these results new derivatives have been developed to improve stability and better efficacy in in-vivo models. These findings provide evidence that targeting AR BF3 pocket using small molecule inhibitors is a viable therapeutic approach for patients with advanced prostate cancer.
- Medicine and Medical Research