Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis

Abstract CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered...

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Veröffentlicht in:Nucleic acids research 2022-03, Vol.50 (5), p.2440-2451
Hauptverfasser: Tan, Yang, Sun, Xueqing, Xu, Yizhu, Tang, Bingjie, Xu, Shuaiqi, Lu, Dong, Ye, Yan, Luo, Xiaomin, Diao, Xu, Li, Fulong, Wang, Tianyi, Chen, Jiayu, Xu, Qiang, Wu, Xingxin
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Sprache:eng
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Zusammenfassung:Abstract CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-β1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkac139