发现含氨基吡啶的螺环衍生物作为 EGFR 突变抑制剂。

Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors.

机构信息

a School of Pharmacy , Guangdong Pharmaceutical University , Guangzhou , China.

b Esa Biotech Co., LTD. , Guangzhou , China.

出版信息

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1233-1246. doi: 10.1080/14756366.2019.1634704.

Neratinib is an oral pan HER inhibitor, that irreversibly inhibits EGFR and HER2 and was proven to be effective against multiple EGFR mutations. In previous study, we reported spiro [indoline-3, 4'-piperidine]-2-ones as anticancer agents. In this study, we designed aminopyridine-containing spiro [indoline-3,4'-piperidine] derivatives using Neratinib and spiro [indoline-3, 4'-piperidine]-2-one compound patented as lead structure, then replaced piperidine with cyclopropane to obtain and replaced indoline with benzmorpholine to get and . We synthesized these compounds and evaluated their residual activities under 0.5 M drug concentration on EGFR and ERBB2. Most of compounds showed stronger inhibition on EGFR-wt and ERBB2, in which showed excellent inhibitory activity with inhibition percentage on EGFR-wt kinase of 7%, 6%, 19%, 27%, respectively and 9%, 5%, 12%, 34% on ERBB2 kinase compared with 2% and 6% of Neratinib.

奈拉替尼是一种口服的泛 HER 抑制剂，可不可逆地抑制 EGFR 和 HER2，已被证明对多种 EGFR 突变有效。在之前的研究中，我们报道了螺[吲哚啉-3,4'-哌啶]-2-酮类化合物作为抗癌剂。在本研究中，我们以尼拉替尼和螺[吲哚啉-3,4'-哌啶]-2-酮化合物为先导结构专利，设计了含氨基吡啶的螺[吲哚啉-3,4'-哌啶]衍生物，然后将哌啶用环丙烷取代得到化合物，并将吲哚啉用苯并吗啉取代得到化合物和。我们合成了这些化合物，并在 0.5M 药物浓度下评估了它们对 EGFR 和 ERBB2 的残留活性。大多数化合物对 EGFR-wt 和 ERBB2 的抑制作用更强，其中化合物显示出优异的抑制活性，对 EGFR-wt 激酶的抑制率分别为 7%、6%、19%、27%，对 ERBB2 激酶的抑制率分别为 9%、5%、12%、34%，而尼拉替尼分别为 2%和 6%。