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.