Novel curcumin analogs to overcome EGFR-TKI lung adenocarcinoma drug resistance and reduce EGFR-TKI-induced GI adverse effects

Bioorganic & Medicinal Chemistry
Koji WadaKuo-Hsiung Lee

Abstract

Curcumin (1) down-regulates the expression as well as phosphorylation of epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells expressing gefitinib-resistant EGFR. Thirty-seven newly synthesized curcumin analogues including dimethoxycurcumin (2, DMC) were evaluated for their effects on EGFR expression as well as phosphorylation in two gefitinib-resistant lung adenocarcinoma cell lines, CL1-5 (EGFR(wt)) and H1975 (EGFR(L858R+T790M)). Based on the identified structure-activity relationships, methoxy substitution at C-3', C-4', or both positions favored inhibitory activity (compounds 1, 2, 5, 8-15, 17, 36), while compounds with more polar substituents were generally less active in both cell lines. Compound 36 with a fluorine substituent at C-6' and its protonated counterpart 2 did not lose activity, suggesting halogen tolerance. In addition, a conjugated linker was essential for activity. Among all evaluated curcumin derivatives, compound 2 showed the best inhibitory effects on both wild-type and mutant EGFR by efficiently inducing gefitinib-insensitive EGFR degradation. Compound 23 also reduced gefitinib-induced gastrointestinal damage in the non-transformed intestinal epithelial cell line IEC-18.

References

Feb 3, 2004·The Oncologist·Román Pérez-Soler

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Citations

May 17, 2019·Expert Opinion on Drug Discovery·Eirini Chainoglou, Dimitra Hadjipavlou-Litina
Apr 25, 2019·International Journal of Molecular Sciences·Ella WillenbacherAndreas Seeber
Jul 7, 2017·Clinical Science·Ajaikumar B KunnumakkaraBharat B Aggarwal
Jul 7, 2018·Molecular and Clinical Oncology·Carlo CapalboPaolo Marchetti
Jun 15, 2019·Journal of Experimental & Clinical Cancer Research : CR·Ping ChenJian Li
Aug 28, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yuan LiangJie Zhang

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