A novel mRNA decay inhibitor abolishes pathophysiological cellular transition

Area of Science:

• Cellular dynamics and RNA metabolism
• Molecular mechanisms of cellular transitions
• Drug discovery for RNA decay pathways

Background:

• mRNA synthesis and decay balance is crucial for cell dynamics and is altered by cellular cues.
• Specific mRNA degradation precedes cellular transitions like differentiation and reprogramming.
• The DDX6-4E-T interaction in processing bodies (PBs) is vital for adipogenesis.

Purpose of the Study:

• To identify compounds inhibiting the DDX6-4E-T protein interaction.
• To investigate the effect of such inhibitors on cellular transitions.
• To explore the potential of RNA decay inhibitors in disease treatment.

Main Methods:

• Screening of α-helix analogs with an alkaloid-like backbone.
• In vitro assays to test inhibition of DDX6-4E-T binding.
• Cellular assays using adipogenesis and epithelial-mesenchymal transition (EMT) models.

Main Results:

• IAMC-00192 was identified as a lead compound that directly inhibits DDX6-4E-T interaction.
• IAMC-00192 suppressed PB formation during adipogenesis and EMT.
• The compound extended mRNA half-life in PBs twofold in the EMT model, significantly suppressing cellular transitions.

Conclusions:

• IAMC-00192 is a novel inhibitor of RNA decay that suppresses key cellular transitions.
• This inhibitor serves as a tool to study RNA decay's role in pathology.
• The findings may lead to the development of first-in-class RNA decay inhibitor drugs.