Tyrosine kinase inhibition: Ligand binding and conformational change in c‐Kit and c‐Abl

2009/08/04 by Eamonn F. Healy, Skylar Johnson, Charles R. Hauser +1 · 1 citation
Chemistry · Medicine · #ABL #Biochemistry #Biology #Biophysics #Cancer research #Chemistry #Chronic Lymphocytic Leukemia Research #Chronic Myeloid Leukemia Treatments #Hydrogen bond #Imatinib #Imatinib mesylate #Kinase #Ligand (biochemistry) #Molecule #Quinazolinone synthesis and applications #Receptor #Receptor tyrosine kinase #Signal transduction #Stereochemistry #Tyrosine kinase

paper · pdf · doi:10.1016/j.febslet.2009.07.051

openalex publication_date 2009/08/04 · openalex created_date 2025/10/10 · openalex updated_date 2026/05/21

Abstract

The conformational flexibility exhibited by protein kinases poses an enormous challenge to the design of cancer therapeutics. Additionally the high degree of structural conservation within the kinase superfamily often leads to inhibitors that exhibit little selectivity and substantial cross reactivity. This work investigates the conformational changes that accompany the binding of Gleevec, or imatinib mesylate, to the tyrosine kinases c-Kit and c-Abl. Our analysis is that this fit is driven, at least in part, by the need to exclude water from solvent-exposed backbone hydrogen bonds. Both experimental and molecular modeling studies of the active state inhibitor of the tyrosine kinase c-Abl indicate that solvent exclusion also plays a role in this system.

Citations

• Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase
• Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model
• Structure of a c-Kit Product Complex Reveals the Basis for Kinase Transactivation
• Dehydron: A Structurally Encoded Signal for Protein Interaction
• CHARMM: A program for macromolecular energy, minimization, and dynamics calculations

Cited by

• Eamonn Healy [wikipedia]

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