基于PROTAC技术的EGFR降解剂的合成

Synthesis of EGFR Degraders Based on PROTAC Technology

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(IC_(50))值分别为8.072 nmol/L和7.675 nmol/L。

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 CompoundⅦcould effeivly indue the degradation of EGFR^(del19/T790M/C797S)and EGFR^(L858R/T790M/C797S)mutant prpteins,and the cell proliferation inhibition activity showed that CompoundⅦcould inhibit Ba/F3-EGFR^(del19/T790M/C797S)and Ba/F3-EGFR^(L858R/T790M/C797S)cell proliferation with IC_(50),values of 8.072 nmol/L and 7.675 nmol/L,respectively.