Dipartimento Farmaceutico, Università degli Studi di Parma, Vle GP Usberti 27/A, I-43124 Parma, Italy.
J Med Chem. 2010 Mar 11;53(5):2038-50. doi: 10.1021/jm901558p.
Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.
不可逆的 EGFR 抑制剂可以避免第一代可逆的 ATP 竞争性抑制剂在治疗非小细胞肺癌中的获得性耐药。它们既包含一个确保靶标识别的驱动基团，又包含一个弹头，通常是丙烯酰胺或炔丙酰胺片段，它与 EGFR 激酶结构域内的 Cys797 共价结合。我们对弹头基团的作用进行了系统的探索，在传统的 4-苯胺基喹唑啉骨架的 6 位引入了不同的半胱氨酸捕获片段。我们发现不同的反应基团，包括环氧化物酰胺（化合物 3-6）和苯氧基乙酰胺（化合物 7-9），能够不可逆地抑制 EGFR。特别是，（2R，3R）-N-（4-（3-溴苯胺基）喹唑啉-6-基）-3-（哌啶-1-基甲基）环氧乙烷-2-甲酰胺（6）以比吉非替尼（1）低得多的浓度抑制 EGFR 自身磷酸化和下游信号通路，抑制增殖，并诱导携带 EGFR T790M 突变的吉非替尼耐药 NSCLC H1975 细胞凋亡。
