Reducing Cabozantinib Toxicity in Renal Cell Carcinoma Treatment through Structural Modifications

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Cabozantinib is a Tyrosine Kinase Inhibitor (TKI) used for Renal Cell Carcinoma (RCC).
• It causes significant side effects including myelosuppression, immunosuppression, and angiopathy.
• Identifying targets for efficacy and toxicity is crucial for safer treatment.

Purpose of the Study:

• To identify key protein targets of cabozantinib responsible for its therapeutic effects and adverse reactions.
• To explore structural modifications of cabozantinib to reduce toxicity while preserving anti-cancer efficacy.
• To provide a basis for designing safer and more effective TKIs for RCC.

Main Methods:

• A computational approach screened 400 potential protein targets using SwissTargetPrediction and ChemBL.
• Molecular docking and Structure-Activity Relationship (SAR) analyses were performed.
• Focus was placed on structural elements contributing to cabozantinib's toxicity.

Main Results:

• Three proteins were identified as mediating anti-tumor effects, and three others were linked to side effects.
• The methoxyphenyl group in cabozantinib formed detrimental hydrogen bonds with toxicity-related proteins.
• Minimizing these off-target interactions could substantially decrease adverse effects.

Conclusions:

• Structural insights into cabozantinib's dual efficacy and toxicity were gained.
• Optimization strategies for TKI design were proposed.
• This research paves the way for developing safer and more effective RCC treatments.