新型大环EGFR抑制剂的合成

Synthesis of Novel Macrocyclic EGFR Inhibitors

表皮生长因子受体(EGFR)是治疗非小细胞肺癌(NSCLC)的有效靶点,但耐药突变极大地限制了1~3代EGFR小分子抑制剂的临床疗效。化合物A是百济神州公司研发的第四代EGFR小分子抑制剂,我们基于大环化技术改造A,设计并合成了6个新型的大环EGFR抑制剂。其中化合物I能高选择性的抑制突变EGFR^(del19/T790M/C797S)和EGFR^(L858R/T790M/C797S),半抑制浓度(IC_(50))值分别为0.22 nmol/L和0.20 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 1~3 generation inhibitors of EGFR.Compound A is a fourth generation EGFR inhibitor developed by BeiGene,Our structure-based medicinal chemistry effort yielded a Macrocyclic inhibitor of the EGFR^(del19/T790M/C797S)and EGFR^(L858R/T790M/C797S)mutants with an IC_(50)of 0.22 nmol/L and 0.20 nmol/L with high selectivity.