Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors

Small-molecule fibroblast growth factor receptor (FGFR) inhibitors have emerged as a promising antitumor therapy. Herein, by further optimizing the lead compound 1 under the guidance of molecular docking, we obtained a series of novel covalent FGFR inhibitors. After careful structure–activity relationship analysis, several compounds were identified to exhibit strong FGFR inhibitory activity and relatively better physicochemical and pharmacokinetic properties compared with those of 1. Among them, 2e potently and selectively inhibited the kinase activity of FGFR1–3 wildtype and high-incidence FGFR2-N549H/K-resistant mutant kinase. Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable antiproliferative activity in FGFR-aberrant cancer cell lines. In addition, the oral administration of 2e in the FGFR1-amplified H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models demonstrated potent antitumor efficacy, inducing tumor stasis or even tumor regression.

小分子成纤维细胞生长因子受体（fibroblast growth factor receptor, FGFR）抑制剂已成为极具前景的抗肿瘤治疗手段。本研究中，我们在分子对接指导下对先导化合物1进行进一步优化，得到了一系列新型共价FGFR抑制剂。经严谨的构效关系分析，我们筛选出数种化合物，其FGFR抑制活性较强，且相较先导化合物1拥有更优异的理化性质与药代动力学特性。其中，化合物2e可强效且选择性地抑制FGFR1-3野生型激酶，以及高发的FGFR2-N549H/K耐药突变激酶的活性。此外，该化合物可抑制细胞内FGFR信号通路，在FGFR异常的癌细胞系中展现出显著的抗增殖活性。另外，在FGFR1扩增的H1581、FGFR2扩增的NCI-H716以及SNU-16肿瘤异种移植模型中，口服给予化合物2e可展现出强效的抗肿瘤功效，能够抑制肿瘤生长甚至实现肿瘤消退。