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Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
Published on: May 16, 2021
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Development of CXCR4 modulators based on the lead compound RB-108
Renren Bai1, Xiaokang Jie1, Jian Sun1
1College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China.
European Journal of Medicinal Chemistry
|April 15, 2019
Summary
Researchers optimized a compound targeting the CXCR4/CXCL12 axis for anti-inflammatory drug development. Compound IIIm demonstrated potent inhibition of cell invasion and reduced inflammation in mice, showing promise as a novel therapeutic candidate.
Area of Science:
- Medicinal Chemistry
- Immunology
- Pharmacology
Background:
- The CXCR4/CXCL12 axis is implicated in tumor metastasis and inflammation.
- CXCR4 is a potential therapeutic target for anti-inflammatory agents.
Purpose of the Study:
- To synthesize and evaluate novel CXCR4 modulators based on the lead compound RB-108.
- To identify potent anti-inflammatory candidates with improved efficacy and pharmacokinetic profiles.
Main Methods:
- Synthesis of CXCR4 modulator derivatives with modified side chains.
- Assessment of CXCR4 binding affinity and cell invasion inhibition.
- Evaluation of anti-inflammatory activity in a carrageenan-induced mouse paw edema model.
- Pharmacokinetic profiling in Sprague-Dawley rats.
Main Results:
- Derivative compounds maintained potent CXCR4 binding affinity.
- Compounds IIb, IIc, IIIg, IIIj, and IIIm effectively inhibited CXCR4-positive cell invasion, surpassing the lead compound.
- Compound IIIm significantly reduced edema in a mouse model.
- Compound IIIm exhibited favorable pharmacokinetic properties, including a 4.77-hour half-life.
Conclusions:
- Compound IIIm emerged as a promising candidate for further development as an anti-inflammatory agent.
- Structural optimization of RB-108 led to derivatives with enhanced anti-inflammatory and anti-metastatic potential.
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