2. Academic Validation
  3. Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

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

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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