Abstract
The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used 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 androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer.
Highlights
There is currently no curative treatment for patients with castration-resistant prostate cancer (CRPC) and the corresponding median survival is estimated at $16 to 18 monthsAuthors' Affiliations: 1Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada; 2School of Medicine, Koc University, Istanbul, Turkey; 3Leibniz Institute for Age Research (FLI), Jena, Germany; 4Institute of Pharmaceutical and Medicinal Chemistry, Westfa€lische Wilhelms-Universita€t, Mu€nster, Germany; and 5Faculty of Pharmacy, Helwan University, Cairo, EgyptNote: Supplementary data for this article are available at Molecular Cancer Therapeutics Online.H
About 700,000 compounds that successfully docked with Glide SP score < À7 in both runs were redocked into the androgen receptor hormone binding site (HBS) using eHiTs program [15]
A total of 130,000 structures were selected that were consistently docked with both algorithms [i.e., having root mean square deviation (RMSD) < 2 Afor the docking poses produced by Glide SP and eHiTs]
Summary
There is currently no curative treatment for patients with castration-resistant prostate cancer (CRPC) and the corresponding median survival is estimated at $16 to 18 months. Authors' Affiliations: 1Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada; 2School of Medicine, Koc University, Istanbul, Turkey; 3Leibniz Institute for Age Research (FLI), Jena, Germany; 4Institute of Pharmaceutical and Medicinal Chemistry, Westfa€lische Wilhelms-Universita€t, Mu€nster, Germany; and 5Faculty of Pharmacy, Helwan University, Cairo, Egypt. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Cherkasov's labs made equal contributions to this work
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