新型FGFR抑制剂3-氨基吡嗪-2-甲酰胺衍生物的设计、合成及生物学评价
Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors.
作者信息
Zheng Jia, Zhang Wei, Ni Dan, Zhao Shuang, He Yi, Hu Junchi, Li Linfeng, Dang Yongjun, Guo Zufeng, Nie Shenyou
机构信息
Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), College of Pharmacy and Department of Urology of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), College of Pharmacy and Department of Breast and Thyroid Surgery of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
出版信息
ACS Med Chem Lett. 2024 Nov 5;15(11):2019-2031. doi: 10.1021/acsmedchemlett.4c00431. eCollection 2024 Nov 14.
FGFR has been considered a crucial oncogenic driver and promising target for cancer therapy. Herein, we reported the design and synthesis of 3-amino--(3,5-dihydroxyphenyl)-6-methylpyrazine-2-carboxamide derivatives as novel FGFR inhibitors. SAR exploration led to the identification of as a pan-FGFR inhibitor with favorable activity against FGFR1-4. Moreover, blocked the activation of FGFR and downstream signaling pathways at the submicromolar level and exhibited potent antitumor activity in multiple cancer cell lines with FGFR abnormalities. Molecular docking was performed to investigate the possible binding modes of within the binding site of FGFR2. These results suggest that compound is a promising candidate for further drug discovery.
成纤维细胞生长因子受体（FGFR）被认为是一种关键的致癌驱动因子，也是癌症治疗中很有前景的靶点。在此，我们报道了3-氨基-（3,5-二羟基苯基）-6-甲基吡嗪-2-甲酰胺衍生物作为新型FGFR抑制剂的设计与合成。通过构效关系（SAR）研究，确定了一种对FGFR1-4具有良好活性的泛FGFR抑制剂。此外，该抑制剂在亚微摩尔水平阻断了FGFR的激活和下游信号通路，并在多种具有FGFR异常的癌细胞系中表现出强大的抗肿瘤活性。进行了分子对接以研究该抑制剂在FGFR2结合位点内的可能结合模式。这些结果表明，该化合物是进一步药物研发的有前途的候选物。
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