Szokol Bálint, Gyulavári Pál, Kurkó Ibolya, Baska Ferenc, Szántai-Kis Csaba, Greff Zoltán, Orfi Zoltán, Peták István, Pénzes Kinga, Torka Robert, Ullrich Axel, Orfi László, Vántus Tibor, Kéri György
Vichem Chemie Research Ltd. , 1022 Budapest, Hungary.
MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University , 1085 Budapest, Hungary.
ACS Med Chem Lett. 2014 Jan 30;5(4):298-303. doi: 10.1021/ml4003309. eCollection 2014 Apr 10.
Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines.
在非小细胞肺癌（NSCLC）的一个亚组中已鉴定出表皮生长因子受体（EGFR）的激活突变，非小细胞肺癌是全球主要的癌症类型之一。应用EGFR酪氨酸激酶抑制剂会因继发性EGFR突变或肝细胞生长因子受体（c-Met）基因扩增而导致获得性耐药。尽管已经报道了几种EGFR和c-Met抑制剂，但能够克服后一种耐药机制的强效双靶点EGFR/c-Met抑制剂迄今尚未见报道，也尚未进入临床试验阶段。在本研究中，我们鉴定出了双靶点EGFR/c-Met抑制剂，并设计了新型N-[4-(喹啉-4-基氧基)-苯基]-联芳基磺酰胺衍生物，该衍生物在纳摩尔范围内可抑制c-Met受体以及野生型和激活突变型EGFR激酶。我们通过蛋白质免疫印迹分析证明，化合物10在细胞水平上抑制EGFR和c-Met磷酸化，并有效抑制NSCLC细胞系活力。
