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

Koji Wada, Jen Yi Lee, Hsin Yi Hung, Qian Shi, Li Lin, Yu Zhao, Masuo Goto, Pan Chyr Yang, Sheng Chu Kuo, Hui Wen Chen, Kuo Hsiung Lee

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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 (EGFRwt) and H1975 (EGFRL858R+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.

Original languageEnglish
Pages (from-to)1507-1514
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number7
DOIs
Publication statusPublished - 2015 Apr 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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