Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy. Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC.

最近，从临床上观察到越来越多的伴随的EGFR突变和ALK重排，但仍然缺乏有效的单药治疗。从ALK抑制剂14（TAE684）开始，我们开发了一种高效的EGFR / ALK双激酶抑制剂化合物18（CHMFL-ALK / EGFR-050），该化合物可有效抑制EGFR L858R，del 19和T790M突变体以及EML4-ALK ，R1275Q，L1196M，F1174L和C1156Y生化突变体。化合物18显着抑制EGFR突变体和EML4-ALK驱动的NSCLC细胞系的增殖。在细胞环境中，它强烈影响EGFR和ALK介导的信号通路，诱导细胞凋亡并将细胞周期阻滞在G0 / G1期。在体内研究中，18在H1975细胞接种的异种移植模型（40 mg / kg / d，TGI：99％）和H3122细胞接种的异种移植模型（40 mg / kg / d，TGI：78％）中显着抑制了肿瘤的生长。化合物18可能是EGFR或ALK个体以及伴随的EGFR / ALK NSCLC的潜在候选药物。