Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.

ID: ALA4414679

Journal: Eur J Med Chem

Title: Discovery of 4,6-pyrimidinediamine derivatives as novel dual EGFR/FGFR inhibitors aimed EGFR/FGFR1-positive NSCLC.

Authors: Xie Z, Wu K, Wang Y, Pan Y, Chen B, Cheng D, Pan S, Guo T, Du X, Fang L, Wang X, Ye F.

Abstract: 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.

CiteXplore: 31846829

DOI: 10.1016/j.ejmech.2019.111943

Patent ID: ┄