针对《生物大分子动态修饰与化学干预重大研究计划》的“从分子、细胞、组织和个体等多个层次开展对生物大分子动态修饰识别及功能发挥的化学干预研究，发现相应的先导化合物”的研究方向，本项目计划重点关注蛋白质的磷酸化和泛素化动态可逆修饰，采用基于蛋白结构的合理药物（探针）分子设计，通过化学生物学与生物化学、结构生物学、细胞生物学、药理学、临床医学等多学科交叉，针对骨髓瘤药物靶点DYRK2激酶，开发高活性同时高特异性的小分子抑制剂，并通过抑制DYRK2的激酶活性来实现对于蛋白酶体磷酸化、泛素化的有效化学干预，进而获得良好的抗肿瘤效果。本项目是目前领域内为数不多的在同一研究中将蛋白质的磷酸化和泛素化两大动态可逆修饰紧密联系起来同时进行研究的项目，它将帮助建立起生物大分子动态修饰与分子靶向药物发现之间的桥梁，对探索生物大分子动态调控过程之间的内在联系机制和原创药物开发具有重要意义。

According to the required research direction, we will focus on the crucial dynamic modifications of functional proteins, such as phosphorylation and ubiquitination. We plan to use the rational design of chemical probe or small molecule drug candidate based on the co-crystal protein structures as a key strategy, and through chemical biology, biochemistry, structural biology, cell biology, pharmacology, as well as translational medicine approaches, to develop potent and selective small molecule anti-myeloma inhibitors targeting the human DYRK2 kinase. We also plan to use the DYRK2 selective chemical probes to further dissecting the important cellular process of how DYRK2 modulates the function of proteasome. This project provides a new approach on how to study protein phosphorylation and ubiquitination in one study, and will generate significant impact to further understanding the novel and crucial biological functions of dynamic protein modifications, and also provide promising drug candidate for the treatment of tumors.