loading page

Direct blockade of AR binding to its target genes for the treatment of advanced prostate cancer by a novel anti-androgen SBF-1
  • +3
  • Ahmed Elgehama,
  • SUN LIJUN,
  • YU BIAO,
  • Yan Shen,
  • Wenjie Guo,
  • Qiang Xu
Ahmed Elgehama
Nanjing University
Author Profile
SUN LIJUN
Shanghai Institute of Organic Chemistry
Author Profile
YU BIAO
Shanghai Institute of Organic Chemistry
Author Profile
Yan Shen
Nanjing University
Author Profile
Wenjie Guo
Nanjing University
Author Profile
Qiang Xu
Nanjing University
Author Profile

Abstract

BACKGROUND AND PURPOSE Targeting AR-DBD is a potential strategy toward the treatment of CRPC, however, rational design of a small molecules targeting AR-DBD is still underdevelopment. EXPERIMENTAL APPROACH MST, ITC and other different assays has been used to confirm the binding of SBF-1 to AR, also CHIP has been used to confirm the blockade of AR binding to its target genes. The associated signaling pathway affected by SBF-1 has been identified by western blotting. Also, mutant AR-LBD and the the AR lacking DBD has led to the identification of the SBF-1 binding location in the AR. KEY RESULTS SBF-1 induced apoptosis and cell cycle arrest in both LNCaP and PC3/AR+ cell lines, also, inhibited the activation of the AR/IGF-1 and IGF1/AKT/FOXO1/PNCA pathways, which evidenced by decreased expression of p-AR, IGF-1, p-AKT, PCNA and Bcl-2. By using multiple methods, we found that SBF-1 could directly bind to AR and block the transcription of its target genes. Moreover, the interaction between SBF-1 and AR-DBD was confirmed, which overcame the re-activation of AR signaling by mutations in the AR-LBD. In the xenograft models of both ARWT and ARmutant prostate cancer, SBF-1 displayed a strong efficacy at very low doses including the inhibition of tumor growth, prolongation of survival time by inhibiting AR signaling. CONCLUSION AND IMPLICATIONS Our study here found a novel identified inhibitor of AR, SBF-1, for the first time, which is different from the current antiandrogens and may serve as a leading compound for the treatment of prostate cancer.