Reducing Cabozantinib Toxicity in Renal Cell Carcinoma Treatment through Structural Modifications

TL;DR

This study explores how modifying the structure of cabozantinib can reduce its side effects in kidney cancer treatment while keeping its effectiveness.

Contribution

The study identifies specific protein targets and structural elements responsible for cabozantinib toxicity, offering a strategy to reduce side effects.

Findings

Three proteins were linked to cabozantinib's anti-tumor effects, and three to its side effects.

The methoxyphenyl group in cabozantinib forms harmful hydrogen bonds with toxicity-related proteins.

Modifying this region could reduce adverse effects without compromising therapeutic efficacy.

Abstract

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.

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.

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.

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.

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