Abstract
Aim:
Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel β-amino-carbonyl-based androgen receptor antagonist.
Methods:
Different isomers of the β-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.
Results:
Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21-1 and 21-2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S).
Conclusion:
Compound 6012-4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo.
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References
Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29.
Blackledge GR, Cockshott ID, Furr BJ . Casodex (bicalutamide): overview of a new antiandrogen developed for the treatment of prostate cancer. Eur Urol 1997; 31: 30–9.
Kolvenbag GJ, Blackledge GR, Gotting-Smith K . Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development. Prostate 1998; 34: 61–72.
Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T, et al. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998; 33: 447–56.
Müderris II, Bayram F, Ozçelik B, Güven M . New alternative treatment in hirsutism: bicalutamide 25 mg/day. Gynecol Endocrinol 2002; 16: 63–6.
Colabufo NA, Pagliarulo V, Berardi F, Contino M, Inglese C, Niso M, et al. Bicalutamide failure in prostate cancer treatment: involvement of Multi Drug Resistance proteins. Eur J Pharmacol 2008; 601: 38–42.
Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009; 138: 245–56.
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324: 787–90.
Schaufele F, Carbonell X, Guerbadot M, Borngraeber S, Chapman MS, Ma AA, et al. The structural basis of androgen receptor activation: intramolecular and intermolecular amino-carboxy interactions. Proc Natl Acad Sci U S A 2005; 102: 9802–7.
Zhou C, Wu G, Feng Y, Li Q, Su H, Mais DE, et al. Discovery and biological characterization of a novel series of androgen receptor modulators. Br J Pharmacol 2008; 154: 440–50.
Ning M, Zhou C, Weng J, Zhang S, Chen D, Yang C, et al. Biological activities of a novel selective oestrogen receptor modulator derived from raloxifene (Y134). Br J Pharmacol 2007; 150: 19–28.
Bohl CE, Miller DD, Chen J, Bell CE, Dalton JT . Structural basis for accommodation of nonsteroidal ligands in the androgen receptor. J Biol Chem 2005; 280: 37747–54.
Sun C, Shi Y, Xu LL, Nageswararao C, Davis LD, Segawa T, et al. Androgen receptor mutation (T877A) promotes prostate cancer cell growth and cell survival. Oncogene 2006; 25: 3905–13.
Ishiguro H, Ishiguro Y, Kubota Y, Uemura H . Regulation of prostate cancer cell growth and PSA expression by angiotensin II receptor blocker with peroxisome proliferator-activated receptor gamma ligand like action. Prostate 2007; 67: 924–32.
Kang Z, Pirskanen A, Jänne OA, Palvimo JJ . Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J Biol Chem 2002; 277: 48366–71.
Bai VU, Cifuentes E, Menon M, Barrack ER, Reddy GP . Androgen receptor regulates Cdc6 in synchronized LNCaP cells progressing from G1 to S phase. J Cell Physiol 2005; 204: 381–7.
Zhang J, Hsu B A JC, Kinseth B A MA, Bjeldanes LF, Firestone GL . Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells. Cancer 2003; 98: 2511–20.
Acknowledgements
We are indebted to Ms Xiao-yan WU for technical assistance. This work was partially supported by grants from the Ministry of Health (2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, and 2013ZX09507002), Shanghai Science and Technology Development Fund (13DZ2290300) and Thousand Talents Program in China.
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Supplementary information is available at Acta Pharmacologica Sinica's website.
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Figure 1
Compound-induced androgen receptor nuclear translocation. (DOC 267 kb)
Figure 2
Cytotoxicity assay. (DOC 994 kb)
Figure 3
In vivo activity of isomer 4 of compound 6012 against LNCaP xenograft tumor in SCID mice. (DOC 833 kb)
Figure 4
Structures of 6012 and its four isomers. (DOC 65 kb)
Figure 5
ORTEP drawing of the X-ray crystal structures of 6012-2, 6012-3 and 6012-4. (DOC 79 kb)
Table 1
Binding of 72 β-amino-carbonyl analogues to androgen receptors (NA: none activity). (DOC 1161 kb)
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Zhang, Zy., Zhu, Yh., Zhou, Ch. et al. Development of β-amino-carbonyl compounds as androgen receptor antagonists. Acta Pharmacol Sin 35, 664–673 (2014). https://doi.org/10.1038/aps.2013.201
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DOI: https://doi.org/10.1038/aps.2013.201
