FLT3和CDK4/6选择性抑制剂的设计、合成与抗肿瘤活性研究

项目名称： FLT3和CDK4/6选择性抑制剂的设计、合成与抗肿瘤活性研究

项目编号： No.81502925

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 卢帅

作者单位： 中国药科大学

项目金额： 17.9万元

中文摘要： CDK4/6可调控细胞周期G1-S过渡，促进细胞开始有丝分裂，在肿瘤细胞中常过度活化。FLT3属于生长因子受体家族，与AML等白血病直接相关，易突变且预后不良。FLT3可通过下游信号通路激活CDK4/6，两者协同促进肿瘤细胞增殖。因而，CDK4/6和FLT3抑制剂可通过对抗有丝分裂信号和阻滞细胞周期等两种机制，发挥协同抗肿瘤作用，且有助于克服耐药性。此前利用基于片段的设计手段发现了一类对CDK4/6、FLT3及其突变型均有良好抑制活性的新颖化合物，在体外可抑制白血病等细胞株的生长，与AT-7519等阳性对照药表现相当。但化合物对CDK1/2的抑制活性也较好，而该抑制作用是导致CDK抑制剂具有较强毒副作用的重要原因。因此项目将在前期基础上，优化分子结构，尝试降低化合物对CDK1/2的活性，同时保持对CDK4/6、FLT3及其突变型的良好活性，为最终获得具有突出抗肿瘤活性的新颖化合物打下基础。

中文关键词： FLT3；CDK4/6；选择性抑制剂；抗肿瘤

英文摘要： CDK4/6 can regulate G1-S transition of cell cycle and promote cells to enter the mitotic phase. They are often highly activated in the tumor cells and one of their specific inhibitors has been approved by FDA. FLT3 is a member of the growth factor receptor family, which is closely related to leukemia, such as AML. Besides, FLT3 mutations often indicate poor prognosis of AML. FLT3 can activate CDK4/6 by its downstream signaling factors, thus promoting the proliferation of tumor cells. Simultaneous inhibition of CDK4/6 and FLT3 will block tumor progress synergistically by antagonizing the mitotic signaling pathways and arresting the cell cycle. And it may help to overcome the drug resistance of tumor cells, too. In early stage of the project, a class of new compounds were discovered with potent CDK4/6 and FLT3 (WT and mutant) inhibitory activities, by using the fragment-based drug design method. They can inhibit the growth of tumor cell lines including the leukemia cell line in vitro, comparable with the performance of the positive control AT-7519. However, these compounds still possessed CDK1/2 inhibitory activity; while CDK1/2 inhibition always induced strong side effects. Therefore, this project will be committed to optimizing the structures of target compounds in order to reduce the inhibitory potency against CDK1/2 and maintain the inhibitory activity against CDK4/6 and FLT3 (WT and mutant). Overall, this project will be a solid foundation for developing novel FLT3 and CDK4/6 specific inhibitors as antitumor drugs.

英文关键词： FLT3;CDK4/6;specific inhibitor;antitumor