Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

被引：18

作者：

Pollock, Julie A. ^{[1
,5
]}

Wardell, Suzanne E. ^{[2
]}

Parent, Alexander A. ^{[1
]}

Stagg, David B. ^{[2
]}

Ellison, Stephanie J. ^{[2
]}

Alley, Holly M. ^{[2
]}

Chao, Christina A. ^{[2
]}

Lawrence, Scott A. ^{[2
]}

Stice, James P. ^{[2
]}

Spasojevic, Ivan ^{[3
,4
]}

Baker, Jennifer G. ^{[2
]}

Kim, Sung Hoon ^{[1
]}

McDonnell, Donald P. ^{[2
]}

Katzenellenbogen, John A. ^{[1
]}

Norris, John D. ^{[2
]}

机构：

[1] Univ Illinois, Dept Chem, Urbana, IL USA

[2] Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC 27708 USA

[3] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[4] Duke Canc Inst, Pharmaceut Res PK PD Core Lab, Durham, NC USA

[5] Univ Richmond, Dept Chem, Richmond, VA 23173 USA

来源：

NATURE CHEMICAL BIOLOGY | 2016年 / 12卷 / 10期

关键词：

HSP90; CHAPERONE; LNCAP CELLS; ANTIANDROGEN; DERIVATIVES; MUTATION; ENZALUTAMIDE; DETERMINANTS; PROGRESSION; ANTAGONISTS; EXPRESSION;

D O I：

10.1038/nchembio.2131

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide) and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR-CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm, bound to heat shock proteins. Thus, we have identified third-generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.

引用

页码：795 / +

页数：9

共 45 条

[1] Overcoming mutation-based resistance to antiandrogens with rational drug design [J].

Balbas, Minna D. ;

Evans, Michael J. ;

Hosfield, David J. ;

Wongvipat, John ;

Arora, Vivek K. ;

Watson, Philip A. ;

Chen, Yu ;

Greene, Geoffrey L. ;

Shen, Yang ;

Sawyers, Charles L. .

ELIFE, 2013, 2

[2] Targeted Next-generation Sequencing of Advanced Prostate Cancer Identifies Potential Therapeutic Targets and Disease Heterogeneity [J].

Beltran, Himisha ;

Yelensky, Roman ;

Frampton, Garrett M. ;

Park, Kyung ;

Downing, Sean R. ;

MacDonald, Theresa Y. ;

Jarosz, Mirna ;

Lipson, Doron ;

Tagawa, Scott T. ;

Nanus, David M. ;

Stephens, Philip J. ;

Mosquera, Juan Miguel ;

Cronin, Maureen T. ;

Rubin, Mark A. .

EUROPEAN UROLOGY, 2013, 63 (05) :920-926

[3] Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma [J].

Bollag, Gideon ;

Hirth, Peter ;

Tsai, James ;

Zhang, Jiazhong ;

Ibrahim, Prabha N. ;

Cho, Hanna ;

Spevak, Wayne ;

Zhang, Chao ;

Zhang, Ying ;

Habets, Gaston ;

Burton, ElizabethA. ;

Wong, Bernice ;

Tsang, Garson ;

West, Brian L. ;

Powell, Ben ;

Shellooe, Rafe ;

Marimuthu, Adhirai ;

Nguyen, Hoa ;

Zhang, Kam Y. J. ;

Artis, Dean R. ;

Schlessinger, Joseph ;

Su, Fei ;

Higgins, Brian ;

Iyer, Raman ;

D'Andrea, Kurt ;

Koehler, Astrid ;

Stumm, Michael ;

Lin, Paul S. ;

Lee, Richard J. ;

Grippo, Joseph ;

Puzanov, Igor ;

Kim, Kevin B. ;

Ribas, Antoni ;

McArthur, Grant A. ;

Sosman, Jeffrey A. ;

Chapman, Paul B. ;

Flaherty, Keith T. ;

Xu, Xiaowei ;

Nathanson, Katherine L. ;

Nolop, Keith .

NATURE, 2010, 467 (7315) :596-599

[4] IMPROVED MICRO-FLUOROMETRIC DNA DETERMINATION IN BIOLOGICAL-MATERIAL USING 33258-HOECHST [J].

CESARONE, CF ;

BOLOGNESI, C ;

SANTI, L .

ANALYTICAL BIOCHEMISTRY, 1979, 100 (01) :188-197

[5] Molecular determinants of resistance to antiandrogen therapy [J].

Chen, CD ;

Welsbie, DS ;

Tran, C ;

Baek, SH ;

Chen, R ;

Vessella, R ;

Rosenfeld, MG ;

Sawyers, CL .

NATURE MEDICINE, 2004, 10 (01) :33-39

[6] A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice [J].

Chen, Desu ;

Liao, Jiayu ;

Li, Na ;

Zhou, Caihong ;

Liu, Qing ;

Wang, Guangxing ;

Zhang, Rui ;

Zhang, Song ;

Lin, Lilin ;

Chen, Kaixian ;

Xie, Xin ;

Nan, Fajun ;

Young, Andrew A. ;

Wang, Ming-Wei .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (03) :943-948

[7] Targeting the androgen receptor pathway in prostate cancer [J].

Chen, Yu ;

Sawyers, Charles L. ;

Scher, Howard I. .

CURRENT OPINION IN PHARMACOLOGY, 2008, 8 (04) :440-448

[8] ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment [J].

Clegg, Nicola J. ;

Wongvipat, John ;

Joseph, James D. ;

Tran, Chris ;

Ouk, Samedy ;

Dilhas, Anna ;

Chen, Yu ;

Grillot, Kate ;

Bischoff, Eric D. ;

Cal, Ling ;

Aparicio, Anna ;

Dorow, Steven ;

Arora, Vivek ;

Shao, Gang ;

Qian, Jing ;

Zhao, Hong ;

Yang, Guangbin ;

Cao, Chunyan ;

Sensintaffar, John ;

Wasielewska, Teresa ;

Herbert, Mark R. ;

Bonnefous, Celine ;

Darimont, Beatrice ;

Scher, Howard I. ;

Smith-Jones, Peter ;

Klang, Mark ;

Smith, Nicholas D. ;

De Stanchina, Elisa ;

Wu, Nian ;

Ouerfelli, Ouathek ;

Rix, Peter J. ;

Heyman, Richard A. ;

Jung, Michael E. ;

Sawyers, Charles L. ;

Hager, Jeffrey H. .

CANCER RESEARCH, 2012, 72 (06) :1494-1503

[9] Endiandrin a, a potent glucocorticoid receptor binder isolated from the australian plant Endiandra anthropophagorum [J].

Davis, Rohan A. ;

Carroll, Anthony R. ;

Duffy, Sandra ;

Avery, Vicky M. ;

Guymer, Gordon P. ;

Forster, Paul I. ;

Quinn, Ronald J. .

JOURNAL OF NATURAL PRODUCTS, 2007, 70 (07) :1118-1121

[10] Alternatively spliced androgen receptor variants [J].

Dehm, Scott M. ;

Tindall, Donald J. .

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