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

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.
AuthorsLeiming Wang, Chiang-Min Cheng, Jun Qin, Mafei Xu, Chung-Yang Kao, Jingjing Shi, Erli You, Wanchun Gong, Laura Pedro Rosa, Peter Chase, Louis Scampavia, Franck Madoux, Timothy Spicer, Peter Hodder, H Eric Xu, Sophia Y Tsai, Ming-Jer Tsai
JournalScience advances (Sci Adv) Vol. 6 Issue 18 Pg. eaaz8031 (05 2020) ISSN: 2375-2548 [Electronic] United States
PMID32494682 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Chemical References
  • COUP Transcription Factor II
  • Orphan Nuclear Receptors
Topics
  • Animals
  • COUP Transcription Factor II (metabolism)
  • Carcinogenesis
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • Orphan Nuclear Receptors (genetics, metabolism)
  • Prostatic Neoplasms (drug therapy, genetics)

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