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Review Article

Recent Advances in Structural Modification Strategies for Lead Optimization of Tyrosine Kinase Inhibitors to Explore Novel Anticancer Agents

[ Vol. 30 , Issue. 24 ]


Fereshteh Azimian and Siavoush Dastmalchi*   Pages 2734 - 2761 ( 28 )


Lead optimization as a bottleneck in the process of drug discovery is conducted to tackle problems associated with poor pharmacokinetics, continuous emergence of drugresistance, adverse side effects and drug-drug interactions of known pharmaceuticals. Due to the intensive application of multi-targeted tyrosine kinase inhibitors (MTKI) in various pathological conditions, optimization of their structures has always been the focus of intensive medicinal chemistry research efforts. The current review portrays the application of scaffold hopping, bioisosterism, structure-based, and hybrid-based drug design methods in the optimization of lead compounds aiming to enhance their usefulness as novel drugs. Then, the review proceeds with examples of structural modifications carried out, particularly on multi-targeted drugs already available on the market. The demonstrated examples cover structural modifications on 7 well-known drugs during the last twenty years. The application of the above-mentioned strategies has led to the generation of 52 new multitargeted tyrosine kinase inhibitors. Most of the optimized compounds showed improved properties compared to their parent lead compound. The rationales behind the applied modifications and the achieved outcomes were discussed to present practical examples to the researchers engaged in the area.


Structural modification, hybridization, tyrosine kinase inhibitors, lead optimization, drug discovery, anticancer agents.


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