基于肿瘤新靶点PAK4激酶结构的药物分子设计与其作用机制研究

恶性肿瘤的治疗长期以来是一个世界性的难题，抗肿瘤新药研发是创新药物研究的热点领域。PAK4激酶在肿瘤细胞侵袭转移中具有重要作用，设计选择性PAK4抑制剂，对发现肿瘤临床治疗药物具有重大意义。在课题组前期对PAK信号通路进行大量研究工作的基础上，针对现有抑制剂结构无特异性、活性无选择性等缺点，结合计算化学、细胞生物学和结构生物学技术，分析靶酶活性位点特征，设计新的抑制剂结构，通过分子对接对新结构进行活性预测，计算其理化性质来评价其成药性。对表现优异的化合物进行化学合成，测定化合物的理化性质，并进行体内和体外抗肿瘤活性测试和作用机制研究。实现X-射线单晶衍射解析PAK4与配体的复合物结构的突破，并通过NMR实验分析化合物片段与PAK4的作用方式，进行基于片段的药物设计。同时对现有上市药物进行相关研究，以发现现有药物的抗肿瘤新用途。该项研究为新型抗肿瘤药物的研发奠定了重要基础。

Cancer is a leading cause of mortality worldwide, and deaths from cancer are projected to continue rising. Lung, stomach, liver, colon and breast cancer cause the most cancer deaths each year. Therefore, the call for the discovery of less toxic, more selective, and more effective agents to treat cancer has become more urgent. P21-activated kinase (PAK4) executes key functions in tumor invasion and metastasis, and thus emerges as an attractive target for cancer therapy. In our previous studies, the protein-ligand interactions,virtual library screening and biological assay were investigated for PAK4 inhibitors discovery. In this project, our aim is to design more potent and selective PAK4 inhibitors by means of techniques from areas of computational chemistry, cell biology and structural biology. The studies will be focused on modification of the lead compound for generating more diverse structures according to the ATP-binding site features, and prediction of the activities and drug-likeness with the aid of molecular docking and ADME/Tox evaluation. The structures with good records of predictive activities and drug-likeness will be synthesized for further in vitro and in vivo biological assay to validate the inhibitory effects. Furthermore, the structural details of PAK4-ligand complex will be identified through X-ray crystallography and NMR experiments. The observed binding modes will be used for further fragment-based inhibitor design. Besides, the above reasearch modes can be used in the virtually screen of the clinic drugs towards PAK4 to discovery their new functions on chemotherapy. Hopefully, our studies will pave a road towards discovering some potent, orally available small-molecule PAK4 inhibitors with significant promise for the treatment of human cancers.