Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted
Wenbin Hong1, Tianyichen Xiao2, Gang Lin3
1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, China; Cancer Research Center of Xiamen University, Xiamen, China; Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, China; The First Affiliated Hospital of Xiamen University, Xiamen, China.
Abstract:
Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-β1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.
Insights
Researchers developed compound A8, a novel drug targeting the nuclear receptor Nur77, to treat liver fibrosis. This compound effectively inhibits hepatic stellate cell activation and shows promise as an anti-fibrotic therapy with minimal toxicity in preclinical models.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Liver fibrosis is a significant health concern, often progressing to cirrhosis, liver cancer, and failure, with limited treatment options.
- Hepatic stellate cell (HSC) activation is a key process in liver fibrosis development.
- The nuclear receptor Nur77 plays a critical role in HSC activation.
Purpose of the Study:
- To develop novel anti-fibrotic agents targeting Nur77.
- To modify the structure of THPN, a known Nur77-binding compound, to create new therapeutic candidates.
- To investigate the anti-fibrotic potential of novel compounds derived from THPN.
Main Methods:
- Synthesis and screening of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbones.
- Crystal structure analysis to determine the binding mode of compound A8 with Nur77.
- Cell-based assays to evaluate the effect of compound A8 on Nur77-AKT interaction and HSC activation.
- In vivo studies using a mouse model of liver fibrosis to assess efficacy and toxicity.
Main Results:
- Compound A8 demonstrated potent and Nur77-dependent inhibition of TGF-β1-induced HSC activation.
- Crystal structure revealed compound A8 binds Nur77 differently than THPN, potentially interfering with Nur77-AKT interaction.
- Compound A8 impeded Nur77-AKT interaction in cell assays, stabilizing Nur77 without activating AKT.
- In vivo, compound A8 suppressed AKT signaling, increased Nur77 levels, attenuated HSC activation, and ameliorated liver fibrosis with no significant toxicity.
Conclusions:
- Compound A8 is a promising anti-fibrotic drug candidate targeting Nur77.
- The mechanism involves disrupting the Nur77-AKT interaction, leading to Nur77 stabilization and reduced HSC activation.
- Further development of Nur77-targeting agents like compound A8 is warranted for liver fibrosis treatment.
More Related Videos
10:42Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines
Published on: January 3, 2018
05:34Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes
Published on: December 16, 2019
Related Concept Videos
01:11Nomenclature of Aromatic Compounds with Multiple Substituents
For disubstituted benzene derivatives, with two groups attached to the benzene ring, three constitutional isomers are possible. For example, consider dimethyl benzene, often called xylene, where the second methyl group can be substituted at the second, third, or fourth carbon. The relative position of the substituents is represented by prefixes ortho, meta, or...
01:07Structure of Benzene: Kekulé Model
He proposed that benzene has a cyclic structure of six carbon atoms attached to one hydrogen atom each, with three alternating pi bonds.
01:14Directing Effect of Substituents: ortho–para-Directing Groups
01:23Nomenclature of Aromatic Compounds with a Single Substituent
01:09Directing Effect of Substituents: meta-Directing Groups
01:22Electrophilic Aromatic Substitution: Sulfonation of Benzene