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 based on parental compound VPC-13566, which demonstrated excellent anti-androgen potency, anti-PSA activity and abrogates androgen-induced proliferation of LNCaP and Enzalutamide-resistant prostate cancer cell lines. These studies resulted with a lead inhibitor that was similar to 13566 in activity while being almost 10-fold more stable in microsomes experiment.This lead compound thus possess drug-like properties that could have great potential for alternative treatment of prostate cancer.