Szokol Bálint, Gyulavári Pál, Baska Ferenc, Ibolya Kurkó, Greff Zoltán, Szántai Kis-Csaba, Zoltán Orfi, Peták István, Axel Ullrich, Vantus Tibor, Kéri György, Orfi László
Vichem Chemie Kutató Kft.
Orvosi Vegytani, Molekuláris Biológiai és Patobiokémiai Intézet, Semmelweis Egyetem.
Acta Pharm Hung. 2013;83(4):121-33.
The epidermal growth factor receptor (EGFR) family has been well-known for more than ten years as the target of non-small lung carcinoma (NSCLC) which is one of the leading cause of mortality among the cancer types. The receptor tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib) which have been applied in the therapy, are not able to inhibit the progression of this disease perfectly because of resistance. It has been demonstrated that the amplification of mesenchymal-epithelial transition factor (c-Met) or secondary mutation of EGFR kinase causes the resistance against EGFR inhibitors in 18-20 percent of the cases. Clinical candidates inhibiting both of EGFR and c-Met kinases are unknown in the literature. We have developed quinoline-based inhibitors in our research project, which inhibit both kinases in submicromolar range in enzymatic assays, moreover we have demonstrated by western blot analysis that these compounds inhibit the autophosphorylation in vivo. The binding of the effective compounds was examined by in silico and docking simulations.
表皮生长因子受体（EGFR）家族作为非小细胞肺癌（NSCLC）的靶点已为人熟知超过十年，NSCLC是癌症类型中主要的致死原因之一。已应用于治疗的受体酪氨酸激酶抑制剂（吉非替尼、厄洛替尼、拉帕替尼）由于耐药性，无法完美抑制该疾病的进展。已证明，间充质上皮转化因子（c-Met）的扩增或EGFR激酶的二次突变在18%-20%的病例中导致对EGFR抑制剂产生耐药性。文献中尚无抑制EGFR和c-Met激酶二者的临床候选药物。我们在研究项目中开发了基于喹啉的抑制剂，其在酶促试验中能在亚微摩尔范围内抑制这两种激酶，此外，我们通过蛋白质印迹分析证明这些化合物在体内抑制自磷酸化。通过计算机模拟和对接模拟研究了有效化合物的结合情况。
