抗肿瘤研究亟需新治疗策略，研发新药物。激活抑癌基因区别于目前主流的靶向抑制原癌基因策略，极具前景和挑战性。我们拟以抑癌基因蛋白酪氨酸磷酸酶SHP1为研究对象，采用别构调节策略开展SHP1高选择性激活剂的发现与抗肿瘤活性研究。前期已建立全长SHP1分子水平高通量筛选体系，完成大于30万化合物的高通量筛选，并通过初筛、复筛、剂量依赖以及选择性实验获得对SHP1的PTP结构域和SHP2全长均无激活作用的14个结构多样化合物。本项目拟在良好工作基础上，进一步开展构效关系优化，发现活性和选择性更好的化合物；并在细胞水平上研究化合物抗Bcr-Abl融合型CML和FLT3突变型AML细胞活性与作用机制；以及整体动物水平抗Bcr-Abl融合型CML和FLT3突变型AML能力，发现选择性高、抑瘤效果强的候选化合物，为针对SHP1为靶标的抗白血病提供新物质基础，为靶向抑癌基因的抗肿瘤药物研究提供新思路。

Anti-tumor research requires new treatment strategies and development of new drugs. Targeting tumor suppressors is promising and challenging, different from the current mainstream targeting of proto-oncogene strategies. Here, the allosteric regulation strategy was used to carry out the tumor suppressor gene tyrosine phosphatase SHP1 high selectivity activator discovery and anti-tumor activity study. A molecular level high throughput screening system targeting full SHP1 was established, and more than 300,000 compounds were screened. There were 14 structurally diverse compounds that showed good selectivity against SHP1 PTP domain of and SHP2 full length ,after screening, re-screening, dose-dependent and selective experiments. The aim of this project is to further improve the structure-activity relationship, to find compounds with better activity and selectivity, and to study the activity and mechanism of the compounds against Bcr-Abl fusion CML and FLT3 mutant AML cells at the cellular level ; And the overall animal level anti-Bcr-Abl fusion CML and FLT3 mutant AML ability, to find high selectivity, tumor inhibition effect of candidate compounds for SHP1 as the target of anti-leukemia to provide a new material basis, for targeting tumor suppressors drug research to provide new ideas.