ARN-509: A novel antiandrogen for prostate cancer treatment Journal Article
| Authors: | Clegg, N. J.; Wongvipat, J.; Joseph, J. D.; Tran, C.; Ouk, S.; Dilhas, A.; Chen, Y.; Grillot, K.; Bischoff, E. D.; Cai, L.; Aparicio, A.; Dorow, S.; Arora, V.; Shao, G.; Qian, J.; Zhao, H.; Yang, G.; Cao, C.; Sensintaffar, J.; Wasielewska, T.; Herbert, M. R.; Bonnefous, C.; Darimont, B.; Scher, H. I.; Smith-Jones, P.; Klang, M.; Smith, N. D.; de Stanchina, E.; Wu, N.; Ouerfelli, O.; Rix, P. J.; Heyman, R. A.; Jung, M. E.; Sawyers, C. L.; Hager, J. H. |
| Article Title: | ARN-509: A novel antiandrogen for prostate cancer treatment |
| Abstract: | Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer. ©2012 AACR. |
| Keywords: | cancer chemotherapy; controlled study; protein expression; unclassified drug; dose response; drug dose comparison; drug efficacy; nonhuman; drug targeting; drug megadose; protein localization; cell proliferation; animal cell; mouse; animals; mice; animal tissue; steady state; animal experiment; animal model; in vivo study; cancer cell culture; drug potency; drug structure; tumor xenograft; xenograft model antitumor assays; cell line, tumor; structure activity relation; prostatic neoplasms; gene expression regulation, neoplastic; cancer regression; transcription regulation; drug distribution; cancer size; androgen antagonists; drug clearance; cellular distribution; androgen receptor; rats; drug bioavailability; maximum plasma concentration; drug blood level; antiandrogen; bicalutamide; receptor blocking; antineoplastic agents, hormonal; receptors, androgen; drug half life; drug dose increase; dna binding; ic 50; drug protein binding; anilides; nitriles; tosyl compounds; castration resistant prostate cancer; phenylthiohydantoin; drug dna binding; thiohydantoins; 4 [3 [4 cyano 3 (trifluoromethyl)phenyl] 5,5 dimethyl 4 oxo 2 thioxo 1 imidazolidinyl] 2 fluoro n methylbenzamide; drug brain level; new drug; arn 509 |
| Journal Title: | Cancer Research |
| Volume: | 72 |
| Issue: | 6 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2012-03-15 |
| Start Page: | 1494 |
| End Page: | 1503 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-11-3948 |
| PROVIDER: | scopus |
| PMCID: | PMC3306502 |
| PUBMED: | 22266222 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 April 2012" - "CODEN: CNREA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work