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

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

来源：Bioorganic & Medicinal Chemistry, 2015, 23(7): 1507-1514.

DOI：10.1016/j.bmc.2015.02.003

• Curcumin
• EGFR
• Gastrointestinal tract
• Lung adenocarcinoma
• Tyrosine kinase inhibitor

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, 815, 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.

• 出版日期2015-4-1
• 单位中国医科大学