Recent development of cyclic amide (pyridone/lactam) moiety containing heterocycles as protein kinase inhibitors.
Recent development of cyclic amide (pyridone/lactam) moiety containing heterocycles as protein kinase inhibitors.
复制标题
最近开发了含有杂环的环酰胺（吡啶酮/内酰胺）部分作为蛋白激酶抑制剂。
DOI：
10.2174/092986710790149747
复制
发表时间：
2010
影响因子：
4.1
通讯作者：
S. Malhotra
中科院分区：
文献类型：
--
作者：
Linyi Wei;S. Malhotra
Staurosporine， pyridone 6和hydroxyfasudil是含有环酰胺（pyridone/lactam）片段的杂环，被发现/开发为有效的蛋白激酶抑制剂，靶向ATP（腺苷-5'-三磷酸）结合袋。尽管分子形状不同（分别为五环、四环和自行车），但它们都以非常相似的方式与蛋白激酶ATP结合袋的铰链区残基结合：环酰胺部分占据ATP结合袋的腺嘌呤区，并通过其氢键受体/供体对与铰链区形成至少两个氢键相互作用。本文以含杂环蛋白激酶抑制剂的环酰胺（吡啶酮/内酰胺）片段为例，综述了它们的治疗应用、激酶抑制的结构基础以及相关的合成方法。基于含有核心支架的环酰胺（吡啶酮/内酰胺）片段的激酶抑制剂偏倚文库的设计、合成和分析可以显著提高高通量筛选（HTS）的效率，加快hit-to-lead过程，提高开发用于治疗各种疾病特别是癌症的蛋白激酶抑制剂的成功率。
Staurosporine, pyridone 6 and hydroxyfasudil are cyclic amide (pyridone/lactam) moiety containing heterocycles that are discovered/developed as potent protein kinase inhibitors targeting on the ATP (Adenosine-5'-triphosphate) binding pocket. Despite different molecular shapes (pentacycle, tetracycle and bicycle, respectively), they all bind to the residues of the hinge region at ATP binding pocket of protein kinases in a very similar manner: the cyclic amide moiety occupies the adenine region of ATP binding pocket and forms at least two hydrogen bonding interaction with the hinge region via its hydrogen bond acceptor/donor pair. Using a few examples of cyclic amide (pyridone/lactam) moiety containing heterocyclic protein kinase inhibitors, this review discusses their therapeutic application, structural basis of kinase inhibition, as well as their associated syntheses. It is anticipated that the design, synthesis and profiling of the kinase inhibitor-biased library based upon the cyclic amide (pyridone/lactam) moiety containing core scaffolds may significantly enhance the efficiency of high-throughput screenings (HTS), accelerate hit-to-lead process and improve the success rate in the development of protein kinase inhibitors for the treatment of various diseases especially cancer.