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.
Curr Med Chem. 2019;26(31):5811-5824. doi: 10.2174/0929867325666180713124223.
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.
酪氨酸激酶是一大类蛋白激酶中的一个亚群，它们将磷酸基团从 ATP 转移到各种氨基酸残基上。通过磷酸化酪氨酸残基，酪氨酸激酶通过信号转导级联反应负责激活各种蛋白质，这是细胞信号传导的普遍机制。许多酪氨酸激酶抑制剂（TKI）在临床成功和蛋白激酶中的致病突变的频繁成功表明，大量激酶可能代表治疗相关的靶点。迄今为止，大多数临床前和临床 TKI 都是 ATP 竞争性的非共价抑制剂，它们通过识别特定蛋白激酶的独特特征来实现其选择性。目前科学界越来越感兴趣的是开发与 ATP 结合口袋中的半胱氨酸或其他亲核残基形成共价键的不可逆抑制剂。不可逆 TKI 具有许多潜在的优势，包括延长药效学、合理的化合物设计适用性、高效力以及通过反应性半胱氨酸残基的突变验证药理学特异性的能力。在这里，我们综述了开发半胱氨酸靶向不可逆 TKI 的最新进展，并讨论了它们的构象模式，这些模式确定了三磷酸腺苷结合口袋及其生物活性。
