Background:

ARN-509, a synthetic biaryl thiohydantoin compound, is a competitive androgen receptor (AR) inhibitor and fully antagonistic to AR overexpression. The IC50 of ARN-509 is 16 nmol/L [1].
AR, included in the steroid receptor superfamily, is important for prostate cell proliferation and male sexual differentiation [2]. AR overexpression is a common and important feature of castration resistant prostate cancer (CRPC) [1].
ARN-509 (1 μmol/L) treatment for 48 hours resulted in increased DNA damage in LNCaP cells, LNCaP-AR cells and VCaP cells. In LNCaP cell line, treatment with ARN-509 (1 μmol/L) resulted in decreased cell survival. Treatment with ARN-509 (1 μmol/L) for 48 hours significantly decreased C-NHEJ–mediated recombination (>60%) in LNCaP cells that had been transfected with V(D)J recombination substrate along with RAG1 and RAG2 expression vectors [3]. ARN-509 showed robust transcriptional and proliferative agonist activity in AR F876L–expressing cells, and promoted AR DNA binding in LNCaP/SRαF876L cells [4].
Orally treated with ARN-509 (10 mg/kg/d) for 17 days, androgendriven luciferase reporter–gene activity in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors (coexpressing exogenous AR and the AR-dependent reporter ARR2-Pb-luc), was consistently reduced. This indicated that ARN-509 inhibited AR in vivo. ARN-509 made tumors exhibit a decrease in proliferative index and an increase in apoptotic rate [1].
参考文献:
[1]. Nicola J. Clegg, John Wongvipat, James D. Joseph, et al. ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment. Therapeutics, Targets & Chemical Biology, 2012, 72(6): 1494-1503.
[2]. Shuyuan Yeh and Chawnshang Chang. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc. Natl. Acad. Sci., 1996, 93: 5517-5521.
[3]. William R. Polkinghorn, Joel S. Parker, Man X. Lee, et al. Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers. Cancer Discovery, 2013, 3(11):1245-53.
[4]. James D. Joseph, Nhin Lu, Jing Qian, et al. A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509. Cancer Discovery, 2013, 3(9):1020-9.