AZD3514: A small molecule that modulates androgen receptor signaling and function in vitro and in vivo

Molecular Cancer Therapeutics

Volumn 12, Issue 9, 2013, Pages 1715-1727

  Loddick, Sarah A ^a   Ross, Sarah J ^a   Thomason, Andrew G ^a   Robinson, David M ^a   Walker, Graeme E ^a   Dunkley, Tom P J ^a,c   Brave, Sandra R ^a,d   Broadbent, Nicola ^a   Stratton, Natalie C ^a   Trueman, Dawn ^a   Mouchet, Elizabeth ^a   Shaheen, Fadhel S ^b   Jacobs, Vivien N ^a   Cumberbatch, Marie ^a   Wilson, Joanne ^a   Jones, Rhys D O ^a   Bradbury, Robert H ^a   Rabow, Alfred ^a   Gaughan, Luke ^b   Womack, Chris ^a   Barry, Simon T ^a   Robson, Craig N ^b   Critchlow, Susan E ^a   Wedge, Stephen R ^a,e   Brooks, A Nigel ^a   more..

^a ASTRAZENECA   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

^c F HOFFMANN LA ROCHE LTD   (Switzerland)

^d Victoria Mill ^*  (United Kingdom)

^e Newcastle Diabetes Centre   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

6 [4 [4 [2 (4 ACETYLPIPERAZI 1 YL)ETHOXY]PHENYL]PIPERADIN 1 YL] 3 (TRIFLUOROMETHYL) 7,8 DIHYDRO[1,2,4]TRIAZOLO [4,3 B]PYRIDAZINE; ABIRATERONE ACETATE; ANDROGEN RECEPTOR; ANTINEOPLASTIC AGENT; AZD 3514; ENZALUTAMIDE; TESTOSTERONE PROPIONATE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CELL NUCLEUS; CELL PROLIFERATION; CELL STRAIN LNCAP; CONTROLLED STUDY; DRUG MECHANISM; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROSTATE TUMOR; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; RAT; SEMINAL VESICLE; SIGNAL TRANSDUCTION;

ANDROGEN RECEPTOR ANTAGONISTS; ANDROSTADIENES; ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; DISEASE MODELS, ANIMAL; DOWN-REGULATION; DRUG SCREENING ASSAYS, ANTITUMOR; GENE EXPRESSION REGULATION, NEOPLASTIC; HCT116 CELLS; HUMANS; MALE; MICE; MICE, NUDE; PHENYLTHIOHYDANTOIN; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT; PYRIDAZINES; RATS; RATS, WISTAR; RECEPTORS, ANDROGEN; SEMINAL VESICLES; SIGNAL TRANSDUCTION; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84884504514     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-12-1174     Document Type: Article

References (47)

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics 2008. CA Cancer J Clin 2008;58:71-96.
2. Huggins C, Hodges CV. Studies on prostatic cancer I the effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin 1972;22:232-40.
3. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005;23:8253-61.
4. Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell 2009;16:458-62.
5. Knudsen KE, Penning TM. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab 2010;21:315-24.
6. Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC. Molecular cell biology of androgen receptor signalling. Int J BiochemCell Biol 2010;42:813-27.
7. Taplin ME. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol 2007;4:236-44.
8. Koivisto P, Visakorpi T, Kallioniemi OP. Androgen receptor gene amplification: a novel molecular mechanism for endocrine therapy resistance in human prostate cancer. Scand J Clin Lab Invest Suppl 1996;226:57-63.
9. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 2001;61: 3550-5.
10. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33-9.
11. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 2001;61: 2892-8.
12. Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 1999;59: 2511-5.
13. Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003;63:149-53.
14. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008;68:4447-54.
15. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008;68:6407-15.
16. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 2006;66:2815-25.
17. Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 2010;28:1496-501.
18. Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, et al. Significant and sustained antitumor activity in post-docetaxel, castration- resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010;28:1489-95.
19. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005.
20. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-46.
21. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: results from the phase III AFFIRM study [abstract]. J Clin Oncol 30, 2012 (suppl 5; abstr LBA1).
22. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-97.
23. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008;26:4563-71.
24. 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.
25. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol 2009;10:981-91.
26. Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012; 72:2176-82.
27. Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res 2011;71:6503-13.
28. Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 2011;17:5913-25.
29. Bradbury RH, Acton DG, Broadbent NL, Brooks AN, Carr GR, Hatter G, et al. Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer. Bioorg Med Chem Lett 2013;23:1945-8.
30. Bradbury RH, Hales NJ, Rabow AA, Walker GE, Acton DG, Andrews DM, et al. Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer. Bioorg Med Chem Lett 2011;21:5442-5.
31. Potter GA, Hardcastle IR, Jarman M. A convenient, large-scale synthesis of abiraterone acetate [h-Acetoxy-17-(3-pyridyl)androsta-5,16- dien], a potential new drug for the treatment of prostate cancer. Org Prep Proc Int 1997;29:123-128.
32. Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C, et al. Structure activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem 2010; 53:2779-96.
33. Veldscholte J, Berrevoets CA, Ris-Stalpers C, Kuiper GG, Jenster G, Trapman J, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol 1992;41:665-9.
34. Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med 1997;3:402-8.
35. Hershberger LG, Shipley EG, Meyer RK. Myotrophic activity of 19- nortestosterone and other steroids determined by modified levator ani muscle method. Proc Soc Exp Biol Med 1953;83:175-80.
36. Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, et al. Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction. Ann N Y Acad Sci 2001;949:44-57.
37. Saitoh M, Takayanagi R, Goto K, Fukamizu A, Tomura A, Yanase T, et al. The presence of both the amino- and carboxyl-terminal domains in the AR is essential for the completion of a transcriptionally active form with coactivators and intranuclear compartmentalization common to the steroid hormone receptors: a three-dimensional imaging study. Mol Endocrinol 2002;16:694-706.
38. Tomura A, Goto K, Morinaga H, Nomura M, Okabe T, Yanase T, et al. The subnuclear three-dimensional image analysis of androgen receptor fused to green fluorescence protein. J Biol Chem 2001;276: 28395-401.
39. Vanaja DK, Mitchell SH, Toft DO, Young CY. Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 2002;7:55-64.
40. Syms AJ, Norris JS, Panko WB, Smith RG. Mechanism of androgenreceptor augmentation. analysis of receptor synthesis and degradation by the density-shift technique. J Biol Chem 1985;260:455-61.
41. Yeap BB, Krueger RG, Leedman PJ. Differential posttranscriptional regulation of androgen receptor gene expression by androgen in prostate and breast cancer cells. Endocrinology 1999;140:3282-91.
42. Smolev JK, Heston WD, Scott WW, Coffey DS. Characterization of the dunning R3327H prostatic adenocarcinoma: an appropriate animal model for prostatic cancer. Cancer Treat Rep 1977;61:273-87.
43. de Pinieux G, Legrier ME, Poirson-Bichat F, Courty Y, Bras-Goncalves R, Dutrillaux AM, et al. Clinical and experimental progression of a new model of human prostate cancer and therapeutic approach. Am J Pathol 2001;159:753-64.
44. Steinberg M. Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer. Clin Ther 2009;31:2312-31.
45. Östling P, Leivonen SK, Aakula A, Kohonen P, Makela R, Hagman Z, et al. Systemic analysis of microRNAs targeting the AR in prostate cancer cells. Cancer Res 2011;71:1956-67.
46. Zhou H, Zhang Y, Hamburger AW. EBP1 inhibits translation of AR mRNA in castration resistant prostate cancer. Anticancer Res 2011; 31:3129-35.
47. Zhou H, Mazan-Mamczarz K, Martindale JL, Barker A, Liu Z, Gorospe M, et al. Postranscription regulation of AR mRNA by an ErbB3-binding protein 1 in prostate cancer. Nucleic Acids Res 2010;38:3619-31.