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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Characterization of a new class of androgen receptor antagonists with potential therapeutic application in advanced prostate cancer
Molecular Cancer Therapeutics, Volume 12, No. 11, Year 2013
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Description
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 ffectively 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. Mol Cancer Ther; 12(11); 2425-35. © 2013 AACR.
Authors & Co-Authors
Li, Huifang
Canada, Vancouver
The University of British Columbia
Hassona, Mohamed D.H.
Canada, Vancouver
The University of British Columbia
Egypt, Helwan
Faculty of Pharmacy
Lack, Nathan A.
Canada, Vancouver
The University of British Columbia
Turkey, Istanbul
Koç Üniversitesi
Axerio-Cilies, Peter
Canada, Vancouver
The University of British Columbia
Leblanc, Eric
Canada, Vancouver
The University of British Columbia
Tavassoli, Peyman
Canada, Vancouver
The University of British Columbia
Kanaan, Natalia
Canada, Vancouver
The University of British Columbia
Frewin, Kate
Canada, Vancouver
The University of British Columbia
Singh, Kriti
Canada, Vancouver
The University of British Columbia
Adomat, Hans
Canada, Vancouver
The University of British Columbia
Böhm, Konrad J.
Germany, Jena
Leibniz Institute on Aging - Fritz Lipmann Institute
Prinz, Helge
Germany, Munster
University of Münster
Guns, Emma S.T.
Canada, Vancouver
The University of British Columbia
Rennie, Paul S.
Canada, Vancouver
The University of British Columbia
Cherkasov, Artem R.
Canada, Vancouver
The University of British Columbia
Statistics
Citations: 15
Authors: 15
Affiliations: 5
Identifiers
ISSN:
15357163
e-ISSN:
15388514
Research Areas
Cancer