靶向ATP活性位点的CDK5抑制剂研究进展

Recent progress of CDK5 inhibitors targeting ATP active sites

细胞周期蛋白依赖性激酶5(cyclin-dependentkinase5,CDK5)是一种丝氨酸/苏氨酸激酶,是CDKs家族的非典型成员,主要被非细胞周期蛋白p35或p39(及各自的截短产物p25或p29)激活,磷酸化下游底物,调控多种神经和非神经功能。研究表明CDK5的异常活化,与多种神经退行性疾病、癌症、糖尿病和炎症等疾病的发生发展密切相关。因此,靶向CDK5已成为多种疾病治疗的重要靶点。然而到目前为止,尚无选择性CDK5抑制剂处于临床阶段。而泛CDK抑制剂存在临床疗效不佳和因广泛抑制其他激酶而引起的不良反应,故临床试验进展缓慢。鉴于此,选择性CDK5抑制剂不论是对阐明CDK5的生物学功能,还是对探索CDK5抑制剂作为安全有效的临床治疗方案都具有重要意义。本文对CDK5的蛋白结构、生物功能、与疾病的关系进行简要概述,重点讨论了靶向ATP活性位点的CDK5抑制剂的结构类型和结合模式,并对开发选择性CDK5抑制剂的策略进行总结与展望。

Cyclin-dependent kinase 5(CDK5),a serine/threonine kinase,is one of the non-typical members of the CDKs family.CDK5 is mainly activated by non-cyclin activators p35 or p39(as well as their respective fragments p25 and p29)to phosphorylate downstream substrates and regulate numerous neural and non-neural functions.Increasing evidence has confirmed that the overactivation of CDK5/p25 complex is closely related to neurodegenerative diseases,cancers,diabetes and inflammation.Consequently,CDK5 has become an important target in multiple diseases treatment.Nevertheless,to date,no selective CDK5 inhibitors are currently in the clinical stage.On the other hand,pan-CDK inhibitors are limited in clinical trials,due to their poor clinical efficacy and toxic side effects caused by the extensive inhibition of other kinases.In view of this,selective CDK5 inhibitors are of great significance not only for elucidating its exact biological functions,but also exploring the possibility of CDK5 inhibitors as a safe and effective therapy.This paper provides a brief overview of the structure and function of CDK5 protein as well as its relationship with diseases.In addition,the structural types and binding modes of CDK5 inhibitors targeting ATP active sites are also highlighted.Finally,we summarize and prospect the strategies to improve the selectivityof CDK5 inhibitors.