State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, And Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu, 610041, China.
School of Life Science and Engineering, Southwest JiaoTong University, Chengdu, Sichuan, 611756, China.
Eur J Med Chem. 2021 Aug 5;220:113499. doi: 10.1016/j.ejmech.2021.113499. Epub 2021 Apr 26.
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 identified 23d as a novel FGFR inhibitor that displayed excellent potency in vitro. Candidate 23d suppressed the phosphorylation of FGFR signaling pathways and induced cell cycle arrest and apoptosis at low nanomolar concentration. In the kinase inhibition profile, 23d showed excellent kinase selectivity for the FGFR family. Furthermore, 23d showed higher aqueous solubility than Erdafitinib. Moreover, 23d exhibited 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 that 23d is a promising candidate for further drug development.
成纤维细胞生长因子受体（FGFRs）信号的异常已被确定为肿瘤发生和许多实体瘤发展的驱动因素，使 FGFR 成为抗癌治疗的一个有吸引力的靶点。在此，我们描述了吡啶并[1,2-a]嘧啶酮衍生物作为有效的 FGFR 抑制剂的设计和合成。结构-活性关系的研究和初步评估确定 23d 是一种新型的 FGFR 抑制剂，在体外具有优异的活性。候选化合物 23d 抑制 FGFR 信号通路的磷酸化，并在低纳摩尔浓度下诱导细胞周期停滞和凋亡。在激酶抑制谱中，23d 对 FGFR 家族表现出优异的激酶选择性。此外，23d 的水溶性高于 Erdafitinib。此外，23d 在 FGFR2 扩增的 SNU-16 胃癌异种移植模型中，以每日口服 30mg/kg 的剂量显示出很强的抗肿瘤活性（肿瘤生长抑制率为 106.4%）。这些结果表明，23d 是进一步药物开发的有前途的候选药物。
