Abstract
Protein kinases are attractive drug targets for numerous human diseases including cancers, diabetes and neurodegeneration. A number of kinase inhibitors that covalently target a cysteine residue in their target kinases have recently entered use in the cancer clinic. Despite the advantages of covalent kinases inhibitors, their inherent reactivity can lead to non-specific binding to other cellular proteins and cause off- target effects in cells. It is thus essential to determine the identity of these off targets in order to fully account for the phenotype and to improve the selectivity and efficacy of covalent inhibitors. Herein we present a detailed protocol for a chemoproteomic method to enrich and identify cellular targets of covalent kinase inhibitors.
Highlights
Protein kinases are a large family of enzymes that transfer the γ-phosphate group of ATP to the tyrosine, serine or threonine residues of substrate proteins modulating numerous biological processes in eukaryotes
Mutations and dysregulation of protein kinases have been implicated in numerous human diseases including cancers, diabetes and neurodegeneration [4, 5]
Frequent occurrence of the disease-causing mutations in protein kinases make them attractive targets for therapeutic discovery
Summary
Protein kinases are a large family of enzymes that transfer the γ-phosphate group of ATP to the tyrosine, serine or threonine residues of substrate proteins modulating numerous biological processes in eukaryotes. 30 kinase inhibitors have been approved by the FDA for treating various types of cancer in the clinic [6]. A small number of kinase inhibitors can form covalent interactions with the sulfurhydryl group of cysteine in protein kinases [8]. A number of covalent kinase inhibitors have entered clinic use.
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