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Published on: January 4, 2016
A Novel FXR-Targeted DUBTAC and Its Applications in Cholestasis Therapy
Ming Cui1,2, Bin Tang1,2, Tingting Yao1,2
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210000, P. R. China.
Abstract:
Farnesoid X receptor (FXR) is critical for cholestatic liver disease therapy, but FXR agonists often show compromised efficacy due to FXR protein degradation under pathological conditions. Here, we report the first discovery of potent FXR DUBTAC stabilizer D11 as a candidate for cholestasis. We designed and synthesized 31 novel compounds by tethering canonical FXR ligands (e.g., OCA, CDCA) to the OTUB1 ligand EN523 via diverse linkers. D11 elevated FXR protein levels in HepG2 cells in a dose- and time-dependent manner, and its action required a functional ubiquitin-proteasome system. It also significantly increased the hepatic FXR protein level in mice with α-naphthylisothiocyanate (ANIT)-induced cholestasis liver injury. Importantly, D11 demonstrated excellent hepatoprotective efficacy against cholestasis with a reliable safety profile. Thus, D11 emerges as a promising lead compound for FXR-targeted cholestasis therapy, paving a new avenue for drug development by stabilizing, rather than merely activating the receptor.
Insights
Researchers discovered D11, a novel compound that stabilizes Farnesoid X receptor (FXR) protein levels. This breakthrough offers a promising new therapeutic strategy for cholestatic liver diseases by preventing protein degradation.
Area of Science:
- Pharmacology
- Hepatology
- Molecular Biology
Background:
- Farnesoid X receptor (FXR) is crucial for treating cholestatic liver diseases.
- FXR agonists often lose efficacy because the receptor degrades under disease conditions.
Purpose of the Study:
- To discover and develop novel FXR stabilizers for cholestasis therapy.
- To investigate a new therapeutic approach by stabilizing FXR instead of activating it.
Main Methods:
- Synthesized 31 novel compounds by linking FXR ligands with an OTUB1 ligand.
- Evaluated compound D11 for its ability to stabilize FXR protein in vitro (HepG2 cells) and in vivo (ANIT-induced cholestasis mouse model).
- Assessed the mechanism of action, requiring a functional ubiquitin-proteasome system.
Main Results:
- Compound D11 significantly increased FXR protein levels in HepG2 cells and in mice with cholestasis.
- D11 demonstrated potent hepatoprotective effects against cholestasis.
- The compound exhibited a favorable safety profile.
Conclusions:
- D11 is a potent FXR deubiquitinase-activating compound (DUBTAC) stabilizer and a promising candidate for cholestasis treatment.
- Stabilizing FXR offers a novel therapeutic avenue for cholestatic liver diseases, overcoming limitations of traditional FXR agonists.
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