关键词：雄激素；肿瘤；前列腺癌；受体位点（生理学）
摘 要：This project is aimed at test the hypothesis that targeting androgen receptor (AR) expression by small-molecule agents represents a potentially successful strategy to block prostate tumor growth and to delay prostate progression. Based on our finding that the AR-ablative agent CG-12 blocked AR expression through the inhibition of glucose uptake, we embarked on the lead optimization of CG-12 to generate novel glucose transporter inhibitors with high potencies in suppressing AR signaling in LNCaP and VCaP cells. These agents inhibited AR expression through -TrCP-mediated Sp1 downregulation, leading to transcriptional repression of the AR gene. By using a structurally optimized derivative, CG-5, the present study demonstrates the therapeutic relevance of targeting the Warburg effect to prostate cancer therapy, in part, through the blockade of AR signaling. Oral CG-5 exhibits in vivo efficacy in suppressing LNCaP-abl xenograft tumor growth in nude mice, and in suppressing the progression of pre-neoplastic prostatic intraepithelial neoplasia progression in TRAMP mice, which correlated with the drug's ability to modulate biomarkers associated with AR signaling.