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Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.ejmech.2019.111943 Zixin Xie 1 , Kaiqi Wu 1 , Yuexuan Wang 1 , Yaqian Pan 1 , Bo Chen 1 , Donghua Cheng 1 , Suwei Pan 1 , Taoning Guo 1 , Xuze Du 1 , Longcheng Fang 1 , Xuebao Wang 1 , Faqing Ye 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.ejmech.2019.111943 Zixin Xie 1 , Kaiqi Wu 1 , Yuexuan Wang 1 , Yaqian Pan 1 , Bo Chen 1 , Donghua Cheng 1 , Suwei Pan 1 , Taoning Guo 1 , Xuze Du 1 , Longcheng Fang 1 , Xuebao Wang 1 , Faqing Ye 1
Affiliation
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FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity 1and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC50 values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
中文翻译：
发现4,6-嘧啶二胺衍生物作为新型双重EGFR / FGFR抑制剂，靶向EGFR / FGFR1阳性NSCLC。
FGF2-FGFR1自分泌途径激活降低了非小细胞肺癌（NSCLC）细胞对吉非替尼等EGFR抑制剂的敏感性。因此，需要具有高选择性和活性的靶向EGFR和FGFR的双特异性药物。通过对优秀的EGFR抑制剂和FGFR抑制剂的结构分析，我们设计并合成了33种4,6-嘧啶二胺衍生物作为EGFR和FGFR双重抑制剂，并在初步细胞筛选后选择BZF 2作为潜在的EGFR和FGFR抑制剂。然后，通过激酶测试和蛋白质印迹分析，将BZF 2定义为具有高选择性1和活性的双重EGFR和FGFR抑制剂。带有FGF2-FGFR1自分泌环的NSCLC细胞系的生物学评估表明，BZF 2显着抑制了细胞增殖（H226和HCC827 GR的IC50值分别为2.11μM和0.93μM，分别），细胞迁移以及诱导的细胞凋亡和细胞周期停滞。体内抗肿瘤活性试验表明，BZF 2明显缩小了肿瘤的大小。因此，BZF 2是一种高度选择性和有效的双重EGFR / FGFR化合物，具有针对EGFR / FGFR1阳性NSCLC的有希望的治疗作用。
更新日期：2019-12-05
中文翻译：
发现4,6-嘧啶二胺衍生物作为新型双重EGFR / FGFR抑制剂，靶向EGFR / FGFR1阳性NSCLC。
FGF2-FGFR1自分泌途径激活降低了非小细胞肺癌（NSCLC）细胞对吉非替尼等EGFR抑制剂的敏感性。因此，需要具有高选择性和活性的靶向EGFR和FGFR的双特异性药物。通过对优秀的EGFR抑制剂和FGFR抑制剂的结构分析，我们设计并合成了33种4,6-嘧啶二胺衍生物作为EGFR和FGFR双重抑制剂，并在初步细胞筛选后选择BZF 2作为潜在的EGFR和FGFR抑制剂。然后，通过激酶测试和蛋白质印迹分析，将BZF 2定义为具有高选择性1和活性的双重EGFR和FGFR抑制剂。带有FGF2-FGFR1自分泌环的NSCLC细胞系的生物学评估表明，BZF 2显着抑制了细胞增殖（H226和HCC827 GR的IC50值分别为2.11μM和0.93μM，分别），细胞迁移以及诱导的细胞凋亡和细胞周期停滞。体内抗肿瘤活性试验表明，BZF 2明显缩小了肿瘤的大小。因此，BZF 2是一种高度选择性和有效的双重EGFR / FGFR化合物，具有针对EGFR / FGFR1阳性NSCLC的有希望的治疗作用。
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