抗FLT3突变型急性髓细胞白血病的Chk1抑制剂的优化及敏感生物标记物研究

急性髓细胞白血病AML是严重威胁人类健康的恶性血液肿瘤之一。检查点激酶Chk1在多种血液肿瘤存在异常高表达，是目前靶向抗肿瘤药物研究的重要靶标。本项目一方面拟在前期自行发现的Chk1抑制剂对AML高度有效的基础上，针对先导物存在潜在的心脏毒性和口服生物利用度差的缺点，通过对先导物的关键药效团采用骨架迁越等方法，并对疏水片段及亲水性侧链进行结构多样性修饰，从而构建新型结构体系。结合自行构建的虚拟筛选模型及类药性预测，择优合成，考察分子、细胞水平的活性及心脏毒性，总结构效/构毒关系，进一步指导化合物的优化设计；另一方面拟在FLT3突变型AML细胞上开展Chk1抑制剂的药物敏感分子作用机制研究，发现Chk1抑制剂的敏感生物标记物，为证实Chk1抑制剂为FLT3突变型AML的潜在特异性治疗药物提供实验依据，为新型的FLT3突变型白血病患者敏感的个性化药物开发提供一种新的思路。

Acute myeloid leukemia is one of hematological malignancies. Checkpoint kinase 1 which is abnormally overexpressed in a variety of hemal tumors is an important target in antitumor drugs research. Aimed at Chk1 inhibitor lead having potential problems of cardiotoxicity and low bioavailability, pharmacophores which can form interactions with key amino acid residues in hinge region of Chk1 were chosen as the basic scaffolds. Using scalfold hopping principles, we construct a series of novel inhibitors based on our previous discovery of Chk1 inhibitors possessing significant AML growth inhibition. For further virtual screening, chemical synthesis, evaluation of antitumor activities in vitro and in vivo, promising candidates for treatment AML will be found and structure-activity relationship/ structure-toxicity relationship will be established. And these achievements are contributed to the research and development of anti-FLT3 mutations AML drugs of independent intellectual property. In the meanwhile, we will study the inhibitory mechanism of these compounds to FLT3 mutation AML and discover the sensitive biomarker for AML, which may lay a solid foundation for promoting the research of Chk1 inhibitors against AML personalized medicine.