Discovery of Imidazo[2,1-b][1,3,4]thiadiazole-Based MNK Inhibitors with Anti-inflammatory Efficacy via Dual...

Area of Science:

• Biochemistry
• Pharmacology
• Immunology

Background:

• Mitogen-activated protein kinase-interacting kinase (MNK) phosphorylates eukaryotic initiation factor 4E (eIF4E).
• MNK signaling is crucial in inflammatory responses, particularly in macrophages.

Purpose of the Study:

• To investigate the role of MNK in LPS-induced inflammation.
• To design and synthesize novel imidazo[2,1-b][1,3,4]thiadiazole derivatives as MNK inhibitors.
• To evaluate the anti-inflammatory and therapeutic potential of these compounds.

Main Methods:

• MNK silencing in LPS-stimulated macrophages.
• Synthesis of imidazo[2,1-b][1,3,4]thiadiazole derivatives.
• In vitro kinase inhibition assays (IC50 determination).
• In vivo studies using LPS-induced inflammation mouse models.

Main Results:

• MNK silencing inhibited eIF4E phosphorylation, inflammatory polarization, and cytokine release.
• Compound 13 potently and selectively inhibited MNK1/2 (IC50 = 10.84/12.81 nM).
• Compound 13 demonstrated dose-dependent anti-inflammatory effects and alleviated organ damage in vivo.
• Compound 13 suppressed eIF4E phosphorylation, NF-κB signaling, macrophage polarization, pro-inflammatory cytokines, and oxidative stress.

Conclusions:

• MNK inhibition is a viable strategy for treating inflammatory diseases.
• Compound 13 represents a promising therapeutic candidate targeting both inflammation and oxidative stress.
• Imidazo[2,1-b][1,3,4]thiadiazole derivatives are effective MNK inhibitors.