Development of erlotinib derivatives as CIP2A-ablating agents independent of EGFR activity.

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Chen KF, Pao KC, Su JC, Chou YC, Liu CY, Chen HJ, Huang JW, Kim I, Shiau CW

Development of erlotinib derivatives as CIP2A-ablating agents independent of EGFR activity.

Bioorg Med Chem. 2012 Oct 15;20(20):6144-53. doi: 10.1016/j.bmc.2012.08.039. Epub 2012 Aug 30.

PubMed ID

22980218 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Erlotinib	Epidermal growth factor receptor	IC 50 (nM)	1360	N/A	N/A	Details