糖尿病肾病(DN)晚期可诱发严重肾功能衰竭，是糖尿病患者的主要致死原因。已有研究表明，IκB激酶β(IKKβ)介导的NF-κB炎症信号通路在DN的发生发展中起着关键作用，抑制IKKβ有望缓解DN。然而，抑制活性及选择性的实现是目前IKKβ抑制剂研究中的瓶颈。我们前期发现在IKKβ结合口袋中，抑制剂IK01嘧啶母核左侧的铰链区以及右侧空白结合区，均存在特异性的结构和氨基酸序列，相异于其他激酶。本项目中，我们拟基于IK01与IKKβ的实际作用模式，针对铰链区特殊的空间和残基序列以及口袋右侧的Cys-46氨基酸，设计并合成一类兼具选择性和高活性的新型吡啶(嘧啶)并杂环类可逆共价抑制剂。测试抑制剂的激酶抑制和选择性，在细胞和动物水平阐明活性化合物抑制高糖诱导的炎症反应和缓解DN的药理药效，并揭示抑制剂与IKKβ选择性作用的分子机制和结构要求，为研发高效、安全的抗DN新药提供新的化学模板和理论依据。

Diabetic nephropathy (DN) is the most commonly complication of diabetes mellitus with high morbidity and mortality all over the word. A large number of studies have shown that the NF-kB signaling pathway induced by IKKβ kinase plays a key role in the development and progression of DN, while the IKKβ inhibitor can markedly block one step of above signals thereby relieve the DN. There are several IKKβ inhibitors have currently used in clinical trials for cancer treatment, most inhibitors display week activity, lack kinase (isoforms) selectivity, and give rise to a variety of side and toxic effects. In our previous study, we found through computer-assisted analysis that the hinge area and binding domain on the right of Ik01 pyrimidine core, gave the great differences in three-dimensional space and the acid residues from other kinases. In our project, based on this finding and the Cys-46 amino acid inside of ATP-binding pocket ofIKKβ, we plan to use the two major types of drug design, rational drug design and structure-based drug design, to design and synthesize a series of novel reversible covalent pyridine (pyrimidine) heterocyclic highly selective inhibitors. Meanwhile, several inhibitors will be chosen to test the inhibition and selectivity between homologous isoforms and other receptor tyrosine kinases, investigating the active compounds’ pharmacological mechanism of inflammatory reaction induced by high glucose and DN in vitro and in vivo, confirming the chemical structure characteristics of ligand and the binding mod of ligand-IKKβ protein through the crystallization of protein-ligand complexes. This project will provide new sites of action and selective and efficient inhibitors targeting IKKβ in DN.