Developing irreversible inhibitors of the protein kinase cysteinome.
Developing irreversible inhibitors of the protein kinase cysteinome.
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DOI：
10.1016/j.chembiol.2012.12.006
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发表时间：
2013-02-21
影响因子：
--
通讯作者：
Gray NS
中科院分区：
文献类型：
--
作者：
Liu Q;Sabnis Y;Zhao Z;Zhang T;Buhrlage SJ;Jones LH;Gray NS
蛋白激酶是一个由大约530个高度保守的酶组成的大家族，它将γ-磷酸基团从三磷酸腺苷转移到多种氨基酸残基，如酪氨酸、丝氨酸和苏氨酸，这是一种普遍存在的细胞信号转导机制。一些激酶导向药物的临床成功和对引起疾病的蛋白激酶突变的频繁观察表明，大量的激酶可能是治疗相关的靶点。到目前为止，大多数临床和临床前的激酶抑制剂都是ATP竞争性的、非共价的抑制剂，它们通过识别特定蛋白激酶的独特特征来实现选择性。最近，人们对开发与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重新产生了兴趣。不可逆激酶抑制剂具有许多潜在的优势，包括延长药效学，适合合理设计，高效，以及通过突变反应性半胱氨酸残基来验证药理特异性。在这里，我们回顾了最近开发半胱氨酸靶向不可逆蛋白激酶抑制剂的努力，并讨论了它们识别ATP结合口袋的模式和它们的生物活性。此外，我们提供了潜在的‘激酶-半胱氨酸体’的信息学评估，并讨论了有效开发新的共价抑制剂的策略。
Protein kinases are a large family of approximately 530 highly conserved enzymes that transfer a γ-phosphate group from ATP to a variety of amino acid residues such as tyrosine, serine and threonine which serves as a ubiquitous mechanism for cellular signal transduction. The clinical success of a number of kinase-directed drugs and the frequent observation of disease causing mutations in protein kinases suggest that a large number of kinases may represent therapeutically relevant targets. To-date the majority of clinical and preclinical kinase inhibitors are ATP-competitive, non-covalent inhibitors that achieve selectivity through recognition of unique features of particular protein kinases. Recently there has been renewed interest in the development of irreversible inhibitors that form covalent bonds with cysteine or other nucleophilic residues in the ATP-binding pocket. Irreversible kinase inhibitors have a number of potential advantages including prolonged pharmacodynamics, suitability for rational design, high potency and ability to validate pharmacological specificity through mutation of the reactive cysteine residue. Here we review recent efforts to develop cysteine-targeted irreversible protein kinase inhibitors and discuss their modes of recognizing the ATP-binding pocket and their biological activity profiles. In addition, we provided an informatics assessment of the potential ‘kinase-cysteinome’ and discuss strategies for the efficient development of new covalent inhibitors.
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