成纤维细胞生长因子受体1(FGFR1)与多种肿瘤的发生发展密切相关，已经成为肿瘤药物治疗的重要靶点。虽然少数FGFR1抑制剂已进入临床研究，但该类药物研发依然存在缺陷：一是单一晶体结构的分子对接模型限制了药物设计的准确性；二是现有抑制剂的激酶选择性较差，易引起诸多毒副作用。我们前期利用分子动力学模拟建立了准确性更高的优化蛋白模型，发现多个具有潜在FGFR1选择抑制活性的吡唑并[3,4-b]吡啶类化合物，为新型FGFR1选择性抑制剂提供了新的结构类型和先导物。本项目中，我们将利用前期筛选出的化合物003为先导，结合基于受体和配体的药物化学方法，设计和合成一系列新颖的吡唑并[3,4-b]吡啶类结构类似物，并测试它们对FGFR1的抑制和选择性，表征其体内外抗肿瘤活性，通过共结晶确证其与FGFR1的结合模式。项目将为以FGFR1为靶标的抗肿瘤药物研究和新型选择性抑制剂的发现提供新的策略和先导。

The Fibroblast Growth Factor Receptor1 (FGFR1) is closely related to the occurrence and development of a variety of tumors, which has become to be a very important target of antitumor drugs treatment. Although some of FGFR1 inhibitors have currently been used in clinical trials, research of this kind of drugs still exist some defects. Firstly, the single crystal structure of molecular docking model limits the accuracy of drug design; secondly, poor kinase selectivity of existing FGFR1 inhibitors gives rise to multiple toxicity and side effects. We have established a optimized protein model of higher accuracy via Molecular Dynamics Simulations, and also discovered some pyrazolo[3,4-b]pyridine derivatives compounds with potential selective inhibitory activity of FGFR1, which have provided a novel structure skeleton and leading compound for new type of FGFR1 selective inhibitors. In this project, based on the leading compound 003, we plan to design and synthesis a series of novel pyrazolo[3,4-b]pyridine structural analogs by medicinal chemistry methods based on the receptor and the ligand, meanwhile, test their inhibitory and selectivity activity to FGFR1, characterize antitumor activities in vitro and vivo, and further confirm their binding mode with FGFR1 by co-crystallization technique. The project will provide new strategy and leading compound for the research of FGFR1 antitumor drugs and discovery of novel FGFR1 selective inhibitors.

成纤维细胞生长因子受体1(FGFR1)与多种肿瘤的发生发展密切相关，已经成为肿瘤药物治疗的重要靶点。虽然少数FGFR1抑制剂已进入临床研究，但该类药物研发依然存在缺陷：一是单一晶体结构的分子对接模型限制了药物设计的准确性；二是现有抑制剂的激酶选择性较差，易引起诸多毒副作用。我们前期利用分子动力学模拟建立了准确性更高的优化蛋白模型，发现多个具有潜在FGFR1选择抑制活性的吡唑并[3,4-b]吡啶类化合物，为新型FGFR1选择性抑制剂提供了新的结构类型和先导物。在本课题中，我们设计、合成了30多个吡唑并[3,4-b]吡啶类和戊二烯酮类衍生物，并通过波谱学手段表征了它们的结构；在激酶和细胞层面对其进行了系统的FGFR1选择抑制活性评价。选取活性较好的化合物，对其作用机制和靶点进行了确认，还初步检测了其体内代谢和抗肿瘤活性。通过本课题的研究，我们发现了具有潜在抗肿瘤活性的FGFR1候选物，为后续此类小分子抑制剂的研发提供了先导化合物。