PT - JOURNAL ARTICLE AU - Wang, Leiming AU - Cheng, Chiang-Min AU - Qin, Jun AU - Xu, Mafei AU - Kao, Chung-Yang AU - Shi, Jingjing AU - You, Erli AU - Gong, Wanchun AU - Rosa, Laura Pedro AU - Chase, Peter AU - Scampavia, Louis AU - Madoux, Franck AU - Spicer, Timothy AU - Hodder, Peter AU - Xu, H. Eric AU - Tsai, Sophia Y. AU - Tsai, Ming-Jer TI - Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment AID - 10.1126/sciadv.aaz8031 DP - 2020 May 01 TA - Science Advances PG - eaaz8031 VI - 6 IP - 18 4099 - http://advances.sciencemag.org/content/6/18/eaaz8031.short 4100 - http://advances.sciencemag.org/content/6/18/eaaz8031.full SO - Sci Adv2020 May 01; 6 AB - The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate its target genes. Mechanistically, the inhibitor directly bound to the COUP-TFII ligand-binding domain and disrupted COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation. Through blocking COUP-TFII’s oncogenic activity in prostate cancer, the inhibitor efficiently exerted a potent antitumor effect in xenograft mouse models and patient-derived xenograft models. Our study identified a potent and specific COUP-TFII inhibitor that may be useful for the treatment of prostate cancer and possibly other diseases.