Accession Number : AD1004506


Title :   Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer


Descriptive Note : Technical Report,30 Sep 2012,29 Sep 2015


Corporate Author : University of British Columbia Vancouver, BC Canada


Personal Author(s) : Cherkasov,Artem ; Rennie,Paul


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1004506.pdf


Report Date : 01 Dec 2015


Pagination or Media Count : 12


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 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.


Descriptors :   PROSTATE CANCER , DRUG THERAPY


Distribution Statement : APPROVED FOR PUBLIC RELEASE