成纤维细胞生长因子受体（FGFR）1属于受体酪氨酸激酶，与多种肿瘤的发生、发展密切相关，其抑制剂可以治疗肿瘤。但目前的抑制剂均作用于FGFR1膜内保守的ATP结合域，缺乏选择性，导致多种副作用和耐药。靶向FGFR1膜外配体结合域可能获得特异性更高的抑制剂。前期工作中，我们发现六肽P48能特异性作用于FGFR1的膜外段并显示出良好的抗肿瘤的效果；更重要的是，P48在FGFR1信号通路中表现出变构抑制的独特效果，但其体内易降解、生物利用度低。我们假设，以P48为先导物，通过化学方法改造其结构中的肽键和非功能氨基酸可能发现一类靶向性更强、生物利用度更高的FGFR1新型变构抑制剂。基于此，本项目拟设计、合成一系列P48类似物并进行抗肿瘤活性测试；深入阐明这类抑制剂变构抑制FGFR1的相关分子机制。项目将为FGFR1膜外抑制剂的研究提供新的分子机制和先导结构，为肿瘤治疗提供新的候选药物。

FGFRs belong to a large family of transmembrane receptor tyrosine kinases (RTK) and play the key role in angiogenesis, transplantation, division and proliferation of several type of cancer. FGFR1 inhibitors can markedly block one step of above signals thereby prevent multiple malignant tumors. However, most of inhibitors bind to the relatively conserved ATP-binding domain in RTKs and lack kinase selectivity, resulting in giving rise to a variety of side and toxic effects. Targeting the extracellular domain of FGFR1 can obtain inhibitores with more selectivity. In our previous study, we found the peptide P48 can specifically binding to the extracellular domain of FGFR1 and inhibit the FGFR1 induced proliferation of cancer cell. More importantly, P48 exhibit an allosteric inhibition against FGFR1-related pathway. We put forward the hypothesis that making P48 as leading compounds, modifying its peptide bond and non-functional amino acid by chemical synthesis could lead to discovery a type of FGFR1 allosteric inhibitor with high specificity, high bioavailability and high stablity. In our project, based on structures of P48, we plan to design and synthesize a series of potent analogues and further explore their selectivity, stablity and inhibit activity toward FGFR1 and FGFR1 induced proliferation of cancer cell. Meanwhile, several inhibitors will be choosed to clarify the molecular mechanism of the allosteric inhibition by structural biology method. The project will provide the structural information and molecular mechanisms of novel FGFR1 extracellular domain inhibitor, and provide a new drug candidates for the treatment of cancer.