Cysteine-Targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions.

Cysteine-Targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions.
Curr Med Chem. 2018 Jul 13;:
Authors: Hu C, Dong X
Abstract
Tyrosine kinases are a subgroup of the larger 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 disease-causing 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 ATP-competitive 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 pattern...

Source: Current Medicinal Chemistry - July 13, 2018 Category: Chemistry Authors: Hu C, Dong X Tags: Curr Med Chem Source Type: research