喹唑啉酮类EGFR变构抑制剂的合成与生物活性研究

Synthesis and biological activity study of quinazolinone EGFR variant inhibitors

表皮生长因子受体(EGFR)是治疗非小细胞肺癌(NSCLC)的有效药物靶点。然而,由于失去了与Cys797的共价相互作用,ECFR的ATP结合口袋处的三级点突变(C797S)诱导了对第三代ECFR抑制剂的耐药性。EAI045是首个针对T790M和C797SEGFR突变体的变构抑制剂。本文通过分析EAI045结构特点,将苯并异吲哚酮部分替换为喹唑啉酮环,设计了新型喹唑啉酮类EGFR变构抑制剂,并通过'HNMR、13C-NMR和HR-MS进行表征确认其结构。随后,采用MTT法评价了该系列化合物对人非小细胞肺癌细胞NCI-H1975的体外抗肿瘤活性。

Epidermal growth factor receptor(EGFR)is an effective drug target for the treatment of non-small cell lung cancer(NSCLC).However,due to the loss of covalent interaction with Cys797,a tertiary point mutation(C797S)at the ATP binding pocket of EGFR induced resistance to third-generation ECFR inhibitors.EAI045 is the first allosteric inhibitor targeting T790M and C797S EGFR mutants.The structural characteristics of EAI045 was analyzed,replacing the benzoindolone with a quinazolone ring,a new quinazolone type EGFR conformational inhibitor was designed,and their structure were conformed through'H NMR,'3C NMR,and HR-MS.Subsequently,the in vitro anti-tumor activity of this series of compounds against human non-small cell lung cancer cell line H-1975 was evaluated using MTT assay.