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Published Online April 9, 2009
Science DOI: 10.1126/science.1168175

Reports

Submitted on November 6, 2008
Accepted on March 13, 2009

Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer

Chris Tran 1{dagger}, Samedy Ouk 2{dagger}, Nicola J. Clegg 1, Yu Chen 3, Philip A. Watson 1, Vivek Arora 1, John Wongvipat 1, Peter M. Smith-Jones 4, Dongwon Yoo 2, Andrew Kwon 1, Teresa Wasielewska 1, Derek Welsbie 5, Charlie Chen 6, Celestia S. Higano 7, Tomasz M. Beer 8, David T. Hung 9, Howard I. Scher 10, Michael Jung 2*, Charles L. Sawyers 11*

1 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2 Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
3 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.; Genitourinary Oncology Service, Division of Solid Tumor Oncology and Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
4 Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
5 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
6 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.; State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
7 Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.
8 Department of Urology, University of Washington, Seattle, WA 98109, USA.
9 Medivation, Inc., 201 Spear Street, San Francisco, CA 94105, USA.
10 Genitourinary Oncology Service, Division of Solid Tumor Oncology and Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
11 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.; Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

* To whom correspondence should be addressed.
Michael Jung , E-mail: jung{at}chem.ucla.edu
Charles L. Sawyers , E-mail: sawyersc{at}mskcc.org

{dagger}These authors contributed equally to this work.

Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here, we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a phase I/II clinical trial, 13 of 30 (43 percent) showed sustained declines (by >50 percent) in serum levels of prostate specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)