Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G.P. Usberti 27/A, I-43124 Parma, Italy.
J Med Chem. 2012 Mar 8;55(5):2251-64. doi: 10.1021/jm201507x. Epub 2012 Feb 17.
Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.
不可逆表皮生长因子受体 (EGFR) 抑制剂含有一个反应性弹头，与激酶结构域中的保守半胱氨酸残基发生共价相互作用。丙烯酰胺片段是一种常用的弹头，可有效烷基化 EGFR 的 Cys797，但它的反应性会导致快速代谢失活或与非靶标发生非特异性反应。我们在这里描述了一系列新的不可逆抑制剂，其中含有在位置 6 连接的 3-氨基丙酰胺，与 4-苯胺基喹唑啉或 4-苯胺基喹啉-3-甲腈的驱动部分相连。这些化合物中的一些在抑制 A549 肺癌细胞中的 EGFR-TK（TK = 酪氨酸激酶）自磷酸化方面与它们的丙烯酰胺类似物一样有效。此外，几种 3-氨基丙酰胺以比吉非替尼低得多的浓度抑制了携带 EGFR 中的 T790M 突变的 gefitinib 耐药 H1975 细胞的增殖。一个典型的化合物，N-(4-(3-溴苯胺基)喹唑啉-6-基)-3-(二甲基氨基)丙酰胺 (5)，在荧光测定中未显示与无细胞 EGFR-TK 的共价结合，而在细胞内环境中选择性激活，释放出可以与巯基反应的丙烯酰胺衍生物。
