Title:Cysteine-targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions
Volume: 26
Issue: 31
Author(s): Chunqi Hu*Xiaowu Dong*
Affiliation:
- College of Chemistry & Chemical Engineering, Shaoxing University, Shaoxing 312000, P.R.,China
- ZJUENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou ,310000, P.R.,China
Keywords:
Cysteine, TKIs, anticancer, EGFR, irreversible, key interaction.
Abstract: Tyrosine kinases are a subgroup of a large class of protein kinases that transfer
phosphate groups from ATP to various amino acid residues. By phosphorylating the tyrosine
residues, the tyrosine kinases are responsible for the activation of various proteins through
signal transduction cascades, which serves as a ubiquitous mechanism of cell signaling. The
frequent success of many tyrosine kinase inhibitors (TKIs) in clinical success and diseasecausing
mutations in protein kinases suggests that a large number of kinases may represent
therapeutically relevant targets. To date, most of the clinical and preclinical TKIs are ATPcompetitive
non-covalent inhibitors, which achieve their selectivity by recognizing the unique
features of specific protein kinases. Of growing interest now in the scientific community is the
development of irreversible inhibitors that form covalent bonds with cysteines or other nucleophilic
residues in the ATP binding pocket. Irreversible TKIs have many potential advantages
including prolonged pharmacodynamics, reasonable compound design suitability, high
potency, and the ability to validate pharmacological specificity by mutations in reactive cysteine
residues. Here, we review recent efforts to develop cysteine-targeting irreversible TKIs
and to discuss their patterns of configuration that identify adenosine triphosphate binding
pockets and their biological activities.
