文献类型：期刊文献

英文题名：Cysteine-targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions

作者：Hu, Chunqi[1];Dong, Xiaowu[2]

机构：[1]Shaoxing Univ, Coll Chem & Chem Engn, Shaoxing 312000, Peoples R China;[2]Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, China 310000, Zhejiang, Peoples R China

年份：2019

卷号：26

期号：31

起止页码：5811

外文期刊名：CURRENT MEDICINAL CHEMISTRY

收录：SCI-EXPANDED(收录号：WOS:000497817000005)、、Scopus(收录号：2-s2.0-85054725069)、WOS

基金：This study was financially supported by Natural Science Foundation of China (No. 81502926 and 81673294) and China Postdoctoral Science Foundation (No. 2017M612017).

语种：英文

外文关键词：Cysteine; TKIs; anticancer; EGFR; irreversible; key interaction

外文摘要：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 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 patterns of configuration that identify adenosine triphosphate binding pockets and their biological activities.