Reducing Cabozantinib Toxicity in Renal Cell Carcinoma Treatment through Structural Modifications
Year: 2025
Type: article
Abstract: BACKGROUND AND OBJECTIVES: Cabozantinib, a Tyrosine Kinase Inhibitor (TKI), is widely used in Renal Cell Carcinoma (RCC) therapy but often causes serious side effects such as myelosuppression, immunosuppression, and angiopathy. This study aims to identify key protein targets responsible for the therapeutic efficacy and adverse reactions of cabozantinib and to explore structural modifications to reduce toxicity while preserving efficacy. METHODS: A non-randomized computational approach was employed, screening 400 potential protein targets using SwissTargetPrediction and ChemBL databases. Molecular docking and Structure-Activity Relationship (SAR) analysis were performed to assess interactions between cabozantinib and identified targets, focusing on structural elements contributing to toxicity. RESULTS: Three primary proteins were identified as responsible for the anti-tumor effects of cabozantinib, while three others were linked to its side effects. Docking analysis revealed that the methoxyphenyl group in cabozantinib formed undesirable hydrogen bonds with toxicity-related proteins. Modulating these off-target interactions by minimizing hydrogen bonding in this region could significantly reduce adverse effects. CONCLUSION: These findings provide structural insights into cabozantinib's dual effects and suggest optimization strategies for TKI design, offering a pathway toward safer and more effective RCC treatments.
Source: Medicinal Chemistry
Authors: Jiaxiang Guo, Xiaotao Yin, Yongliang Lu, Yu Yang
Institution: Chinese PLA General Hospital
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: hybrid
OpenAlex ID: W4409623912