基于STAT3突变的抑制剂发现及其抗淋巴细胞白血病的作用和机制研究

淋巴细胞白血病中高频率突变的STAT3与疾病的发生和恶化密切相关。已报道的STAT3抑制剂基本上都是靶向野生型，而对于突变体则缺乏深入研究。但不依赖于上游刺激就能自我活化的STAT3功能获得型突变体作为内源性信号如何驱动白血病发生和恶化还不清晰。近期我们研究发现WZ系列化合物能特异性靶向突变体且显示较强的抗癌活性，并初步揭示了作用机制。本项目拟在前期基础上：1）依据突变体的结构特点，采用基于结构的合理药物设计策略，对WZ系列化合物进行优化，以发现活性强且特异性靶向突变体的抑制剂，并利用多种细胞模型和PDX动物模型明确其抗癌效果；2）以抑制剂为研究工具并结合Crisper/Cas9，ChIP-seq等手段，明确STAT3突变体驱动癌症发生和恶化的分子机制。本项目有望明确STAT3突变体在淋巴细胞白血病中作为药物靶点的可行性并揭示其药理学机制，为进一步开发临床抗癌药物提供候选药物和理论依据。

High frequency of STAT3 mutations in lymphocytic leukemia are closely associated with the carcinogenesis and progression. The reported STAT3 inhibitors are targeting wild type STAT3，without consideration of the mutant STAT3 with gain-of-function mutations. The STAT3 with gain-of-function mutations could be persistently activated by itself without the stimulation from upstream, the mechanism how mutant STAT3 drive the carcinogenesis and progression lymphocytic leukemia is unclear. We found WZ series compounds could target mutant STAT3 and showed good anti-tumor potency in our previous work. Here, we propose to: 1) employ multiple approaches to get novel inhibitor targeting mutant STAT3 basing the structure characters of mutant STAT3, with high potency and high specificity, and explore the anti-tumor effect and mechanism with multiple cell models and PDX mouse model; 2) utilize the inhibitor as a research tool, with Crispr/Case9 gene edition, ChIP-seq and other methods to address the role of mutant STAT3 in carcinogenesis, metastasis , progression and cancer drug resistance. This project will reveal whether the mutant STAT3 could be a drug target and its pharmacology mechanisms, and provide candidate compounds for future clinical development, new strategies to treat lymphocytic leukemia with mutant STAT3.