Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, ROC.
Bioorg Med Chem. 2012 Oct 15;20(20):6144-53. doi: 10.1016/j.bmc.2012.08.039. Epub 2012 Aug 30.
Cancerous inhibitor of PP2A (CIP2A) is a novel human oncoprotein that inhibits PP2A, contributing to tumor aggressiveness in various cancers. Several studies have shown that downregulation of CIP2A by small molecules reduces PP2A-dependent phosphorylation of Akt and induces cell death. Here, a series of mono- and di-substituted quinazoline and pyrimidine derivatives based on the skeleton of erlotinib (an EGFR inhibitor) were synthesized and their bioactivities against hepatocellular carcinoma were evaluated. The di-substituted quinazoline and pyrimidine derivatives were more potent inhibitors of cancer-cell proliferation than the mono-substituted derivatives. In particular, compound 1 with chloride at position 2 of quinazoline was as potent as erlotinib in inducing cell death but no inhibition for EGFR activity. Further assays confirmed a correlation between cell death, and CIP2A and Akt inhibition by these derivatives. Among all the derivatives, compounds 19 and 22 showed the most potent antiproliferative activities and the strongest inhibition of CIP2A and p-Akt expression.
癌性蛋白磷酸酶 2A（PP2A）抑制剂（CIP2A）是一种新型的人类癌蛋白，可抑制 PP2A，促进多种癌症的侵袭性。多项研究表明，小分子下调 CIP2A 可减少 Akt 的 PP2A 依赖性磷酸化，并诱导细胞死亡。在此，基于厄洛替尼（EGFR 抑制剂）骨架合成了一系列单取代和二取代的喹唑啉和嘧啶衍生物，并对其抗肝癌活性进行了评价。二取代的喹唑啉和嘧啶衍生物比单取代的衍生物对癌细胞增殖的抑制作用更强。特别是，喹唑啉 2 位上带有氯的化合物 1 诱导细胞死亡的能力与厄洛替尼相当，但对 EGFR 活性没有抑制作用。进一步的实验证实了这些衍生物诱导细胞死亡与抑制 CIP2A 和 Akt 的活性之间存在相关性。在所有的衍生物中，化合物 19 和 22 表现出最强的抗增殖活性和最强的抑制 CIP2A 和 p-Akt 表达的能力。
