Abstract 1812: Development of Erlotinib derivatives as CIP2A inhibitors

Abstract PP2A is a protein phosphatase which involves in negatively regulating cell proliferation, survival and differentiation. Literature has shown that cancerous inhibitor of PP2A (CIP2A) is an inhibitor of PP2A in cancer cells. Overexpression of CIP2A contributes to tumor aggressiveness and renders resistance to chemotherapy. Inhibiton of CIP2A by small molecules shut off the downstream signal pathway of Akt through increasing PP2A phosphatase activity. For example, Bortezomib, a poteasome inhibitor, suppressed expression level of CIP2A and further reduced phospho-Akt in hepatocellular carcinoma cells. Hence, Agents that can repress CIP2A have potentials for the treatment in cancers. Erlotinib, an EGFR inhibitor, shows therapeutic effects in clinical. Our data show that CIP2A represents a major factor whereby erlotinib derivatives induce apoptosis in HCC cells. Here, a series of mono- and di-substituted erlotinb derivatives were synthesized and their bioactivities against hepatocellular carcinoma were evaluated. The di-substituted erlotinib derivatives were more potent inhibitors of cancer-cell proliferation than the mono-substituted derivatives. Further assays confirmed a correlation between cell death, and CIP2A and Akt inhibition by these derivatives. Among them, compound 19 provides a proof of concept for the design of a new class of agents that repress CIP2A activity in HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1812. doi:1538-7445.AM2012-1812