Direct blockade of AR binding to its target genes for the treatment of
advanced prostate cancer by a novel anti-androgen SBF-1
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.