Characterization of a new class of androgen receptor antagonists with potential therapeutic application in advanced prostate cancer.
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.
Corresponding Author: Artem Cherkasov, Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6. artc@interchange.ubc.ca.
Huifang
H
Li
Mohamed D H
MD
Hassona
Nathan A
NA
Lack
Peter
P
Axerio-Cilies
Eric
E
Leblanc
Peyman
P
Tavassoli
Natalia
N
Kanaan
Kate
K
Frewin
Kriti
K
Singh
Hans
H
Adomat
Konrad J
KJ
Böhm
Helge
H
Prinz
Emma Tomlinson
ET
Guns
Paul S
PS
Rennie
Artem
A
Cherkasov
D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000873:Anthracenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D001597:Benzylidene Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D016208:Databases, Factual; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D059002:Androgen Receptor Antagonists; D000873:Anthracenes; D001549:Benzamides; D001597:Benzylidene Compounds; D009570:Nitriles; D011944:Receptors, Androgen; C000589257:VPC-3033; D010669:Phenylthiohydantoin; C540278:enzalutamide