Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer

A novel
series of pyridin-3-amine derivatives were designed, synthesized,
and evaluated as multitargeted protein kinase inhibitors for the treatment
of non-small cell lung cancer (NSCLC). Hit 1 was first
disclosed by in silico screening against fibroblast growth factor
receptors (FGFR), which was subsequently validated by in vitro experiments.
The structure–activity relationship (SAR) of its analogues
was then explored to afford novel FGFR inhibitors 2a–2p and 3a–3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3. Interestingly,
compound 3m not only inhibited various phosphorylation
and downstream signaling across different oncogenic forms in FGFR-overactivated
cancer cells but also showed nanomolar level inhibition against several
other NSCLC-related oncogene kinases, including RET, EGFR, EGFR/T790M/L858R,
DDR2, and ALK. Finally, in vivo pharmacology evaluations of 3m showed significant antitumor activity (TGI = 66.1%) in
NCI-H1581 NSCLC xenografts with a good pharmacokinetic profile.

本研究设计、合成并评估了一系列新型吡啶-3-胺（pyridin-3-amine）衍生物，将其作为多靶点蛋白激酶抑制剂用于非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗。先导化合物1最初通过针对成纤维细胞生长因子受体（fibroblast growth factor receptors, FGFR）的虚拟筛选（in silico screening）得到，并经体外实验（in vitro experiments）验证。随后，本研究对其类似物的构效关系（structure–activity relationship, SAR）展开探索，获得了新型FGFR抑制剂2a–2p与3a–3q。其中，化合物3m对FGFR1、FGFR2及FGFR3均展现出强效抑制活性。值得注意的是，化合物3m不仅可在FGFR过度激活的癌细胞中抑制多种致癌突变体的磷酸化过程及其下游信号通路，还对多种非小细胞肺癌相关的致癌基因激酶展现出纳摩尔级抑制活性，包括RET、EGFR、EGFR/T790M/L858R、DDR2及ALK。最后，对化合物3m开展的体内药理学评价结果显示，其在NCI-H1581非小细胞肺癌异种移植模型中展现出显著的抗肿瘤活性（肿瘤生长抑制率TGI = 66.1%），且具备良好的药代动力学特征。