Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases

Area of Science:

• Pharmacology
• Molecular Biology
• Natural Products Chemistry

Background:

• Aberrant activation of Signal Transducer and Activator of Transcription 3 (STAT3) and Nuclear Factor-kappa B (NF-κB) signaling pathways is implicated in cancer and inflammatory diseases.
• Janus Kinases (JAKs) and Inhibitor of Nuclear Factor-kappa B Kinases (IKKs) are key regulators of STAT3 and NF-κB, respectively, making them crucial drug targets.

Purpose of the Study:

• To identify and characterize natural compounds that can inhibit both STAT3 and NF-κB signaling pathways.
• To evaluate xanthatin, isolated from Xanthium L., as a potential therapeutic agent for diseases driven by these pathways.

Main Methods:

• In vitro assays to assess the inhibitory activity of xanthatin on STAT3 and NF-κB signaling.
• Covalent inhibitor studies to determine the mechanism of action and specific binding sites.
• Cell-based assays using cancer cell lines with constitutively activated STAT3 and p65.

Main Results:

• Xanthatin acts as a covalent inhibitor, with its activity dependent on its α-methylene-γ-butyrolactone group.
• Xanthatin preferentially targets Cys243 of JAK2 and Cys412/Cys464 of IKKβ, leading to their inactivation.
• The compound demonstrated preferential inhibition of cancer cell lines exhibiting constitutive activation of STAT3 and p65.

Conclusions:

• Xanthatin is a potent inhibitor of both STAT3 and NF-κB signaling pathways.
• Its covalent interaction with JAK2 and IKKβ underlies its inhibitory effects.
• Xanthatin represents a promising natural compound candidate for the development of novel anticancer and anti-inflammatory drugs.