Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

  • Sci Adv. 2020 Apr 29;6(18):eaaz8031. doi: 10.1126/sciadv.aaz8031.
Leiming Wang  1 ,  Chiang-Min Cheng  1 ,  Jun Qin  2 ,  Mafei Xu  1 ,  Chung-Yang Kao  1 ,  Jingjing Shi  3 ,  Erli You  3 ,  Wanchun Gong  3 ,  Laura Pedro Rosa  4 ,  Peter Chase  4 ,  Louis Scampavia  4 ,  Franck Madoux  4 ,  Timothy Spicer  4 ,  Peter Hodder  4 ,  H Eric Xu  3 ,  Sophia Y Tsai  1  5 ,  Ming-Jer Tsai  1  5
Affiliations
  • 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2. CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 3. CAS Key Laboratory of Receptor Research, VARI-SIMM Center, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. Scripps Research, Molecular Screening Center, Jupiter, FL 33458, USA.
  • 5. Department of Medicine and Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
PMID: 32494682 DOI: 10.1126/sciadv.aaz8031
Abstract

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.

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