Design, synthesis and biological evaluations of a series of Pyrido[1,2-a] pyrimidinone derivatives as novel selective FGFR inhibitors
Design, synthesis and biological evaluations of a series of Pyrido[1,2-a] pyrimidinone derivatives as novel selective FGFR inhibitors
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一系列新型选择性 FGFR 抑制剂吡啶并[1,2-a]嘧啶酮衍生物的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2021.113499
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发表时间：
2021
影响因子：
6.7
通讯作者：
Yu Luoting
中科院分区：
文献类型：
--
作者：
Ran Kai;Zeng Jun;Wan Guoquan;He Xiaojie;Feng Zhanzhan;Xiang Wang;Wei Wei;Hu Xiang;Wang Ningyu;Liu Zhihao;Yu Luoting
成纤维细胞生长因子受体（FGFR）的异常信号传导已被鉴定为肿瘤发生和许多实体瘤发展的驱动因素，使得FGFR成为抗癌治疗的引人注目的靶标。在此，我们描述了作为有效的FGFR抑制剂的吡啶并[1，2-a]嘧啶酮衍生物的设计和合成。结构-活性关系的检查和初步评估确定23是一种新型的FGFR抑制剂，在体外显示出优异的效力。在低纳摩尔浓度下，替吉奥23 d抑制FGFR信号通路的磷酸化，并诱导细胞周期停滞和凋亡。在激酶抑制谱中，23 d对FGFR家族显示出优异的激酶选择性。此外，23 d显示出比Erdafitinib更高的水溶性。此外，23在FGFR 2扩增的SNU-16胃癌异种移植模型中使用30 mg/kg的每日口服剂量显示出有效的抗肿瘤活性（肿瘤生长抑制= 106.4%）。这些结果表明，23是一个有希望的候选药物进一步开发。
Aberrant signaling of fibroblast growth factor receptors (FGFRs) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFRs a compelling target for anticancer therapy. Herein, we describe the design and synthesis of pyrido[1,2-a]pyrimidinone derivatives as potent FGFR inhibitors. Examination of structure–activity relationships and preliminary assessment identified23das a novel FGFR inhibitor that displayed excellent potencyin vitro. Candidate23dsuppressed the phosphorylation of FGFR signaling pathways and induced cell cycle arrest and apoptosis at low nanomolar concentration. In the kinase inhibition profile,23dshowed excellent kinase selectivity for the FGFR family. Furthermore,23dshowed higher aqueous solubility than Erdafitinib. Moreover,23dexhibited potent antitumor activity (tumor growth inhibition = 106.4%) in FGFR2-amplified SNU-16 gastric cancer xenograft model using a daily oral dose of 30 mg/kg. These results suggest that23dis a promising candidate for further drug development.