Stability and Degradation-based Proteome Profiling Reveals Cannabidiol as a Promising CDC123-eIF2γ Inhibitor for...

Area of Science:

• Drug Discovery
• Proteomics
• Cancer Biology

Background:

• Natural products (NPs) offer diverse therapeutic potential but identifying their molecular targets is challenging.
• Understanding NP mechanisms requires advanced target identification strategies.
• Protein-protein interactions (PPIs) are crucial in disease pathways.

Purpose of the Study:

• To introduce stability- and degradation-based proteome profiling (SDPP) for enhanced NP target identification.
• To identify novel targets and mechanisms of action for natural products.
• To evaluate cannabidiol (CBD) as a therapeutic agent for colorectal cancer (CRC).

Main Methods:

• Developed and applied stability- and degradation-based proteome profiling (SDPP).
• SDPP integrates thermal stability and degradation activity for dual protein regulation.
• Utilized SDPP to identify CBD's molecular target in colorectal cancer cells.

Main Results:

• SDPP precisely identified NP targets by analyzing protein stability and degradation.
• Cannabidiol (CBD) was identified as a novel inhibitor of the CDC123-eIF2γ protein-protein interaction (PPI).
• CBD disrupts the oncogenic CDC123-eIF2γ complex, inducing apoptosis in colorectal cancer cells.

Conclusions:

• SDPP is a robust framework for identifying natural product targets.
• CBD is a first-in-class natural PPI inhibitor with therapeutic potential for colorectal cancer.
• Targeting the CDC123-eIF2γ complex offers a selective strategy for CRC treatment.