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.