title: Development of erlotinib derivatives as CIP2A-ablating agents independent of EGFR activity.
abstract: 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.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, ROC.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.forename: Kuan-Chuan
authors.initials: KC
authors.lastname: Pao
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Chou
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: InKi
authors.initials: I
authors.lastname: Kim
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C578265:N2-benzyl-N4-(3-ethynylphenyl)-6,7-dimethoxyquinazoline-2,4-diamine; C578264:N4-(3-ethynylphenyl)-6,7-dimethoxy-N2-(4-phenoxyphenyl)quinazoline-2,4-diamine; D011743:Pyrimidines; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D054648:Protein Phosphatase 2; C030986:pyrimidine