ARN-509: a novel anti-androgen for prostate cancer treatment
By N. J. Clegg, John Wongvipat, J. Joseph, C. Tran, Samedy Ouk, Anna Dilhas, Yu Chen, Kate Grillot, E. Bischoff, Ling Cai and 25 more. Cancer Research, 2012
624 citations recorded by the source corpus.
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 this 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/day of ARN-509, whereas the same response required 100 mg/kg/day 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.
Subfields: Cancer Research, Genetics, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/4121f23f41c266ea7e3a948934ba760a4e7d752d
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Citations in the corpus
- Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor Blockade (2013, positive): “These efforts yielded three second-generation antiandrogens: enzalutamide, ARN-509, and RD162 (Tran et al., 2009; Clegg et al., 2012).”