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.

中文翻译：

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新型多取代的Pyridin-3-amine衍生物作为多靶点蛋白激酶抑制剂的设计，合成和药理评价，用于治疗非小细胞肺癌

设计，合成和评估了一系列新颖的吡啶-3-胺衍生物，作为多靶点蛋白激酶抑制剂用于非小细胞肺癌（NSCLC）的治疗。首先通过计算机筛选针对成纤维细胞生长因子受体（FGFR）的命中1，随后通过体外实验对其进行了验证。然后研究其类似物的结构-活性关系（SAR），以提供新型FGFR抑制剂2a - 2p和3a - 3q。其中3m对FGFR1、2和3表现出有效的抑制作用。有趣的是，化合物3m不仅抑制FGFR过度激活的癌细胞中不同致癌形​​式的各种磷酸化和下游信号传导，而且还显示出对数种其他NSCLC相关癌基因激酶（包括RET，EGFR，EGFR / T790M / L858R，DDR2和ALK）的纳摩尔水平抑制作用。最后，3m的体内药理学评估显示具有良好药代动力学特征的NCI-H1581 NSCLC异种移植物具有显着的抗肿瘤活性（TGI = 66.1％）。