【摘要】 表皮生长因子受体（EGFR）是治疗非小细胞肺癌（NSCLC）的有效靶点，但获得性耐药极大地限制了EGFR小分子抑制剂的临床疗效。PROTAC技术有望通过蛋白降解克服耐药性问题。基于PROTAC技术设计并合成了6个靶向EGFR的降解剂，并进行了药理活性评价。Western blot测试结果显示化合物Ⅶ能有效地诱导EGFR^{del19/T790M/C797S}和EGFR^{L858R/T790M/C797S}突变蛋白的降解，细胞增殖抑制活性测试显示化合物Ⅶ能抑制Ba/F3-EGFR^{del19/T790M/C797S}和Ba/F3-EGFR^{L858R/T790M/C797S}细胞的增殖，半抑制浓度(IC₅₀)值分别为8.072 nmol/L和7.675 nmol/L。更多还原

【Abstract】 Epidermal growth factor receptor（EGFR） is a potent target for the treatment of non-small cell lung cancer（NSCLC）,however acquired resistance greatly limits the clinical efficacy of small molecule inhibitors of EGFR.PROTAC technology holds promise for overcoming resistance by protein degradation.Based on PROTAC technology, six EGFR-targeting degraders were designed and synthesized, and their pharmacological activities were evaluated.The results of protein degradation activity test showed that Compound VII could effectively induce the degradation of EGFR^{del19/T790M/C797S} and EGFR^{L858R/T790M/C797S} mutant proteins, and the cell proliferation inhibition activity showed that Compound VII could inhibit Ba/F3-EGFR^{del19/T790M/C797S} and Ba/F3-EGFR^{L858R/T790M/C797S} cell proliferation with IC₅₀ values of 8.072 nmol/L and 7.675 nmol/L,respectively.更多还原