Development of p62-Keap1 protein–protein interaction inhibitors as doxorubicin-sensitizers against non-small cell lung cancer

Aberrant hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported in non-small cell lung cancer through overexpression of the p62/sequestosome1 protein, resulting in the acquisition of malignancy and drug resistance. We previously discovered compounds termed K67 and KOA153 that overcome chemotherapy resistance in human hepatocellular carcinoma cell lines by inhibiting the protein–protein interactions between p62 and Kelch-like ECH-associated protein 1 (Keap1), an Nrf2 suppressor. Herein, we synthesized analogs of K67 and KOA153 and investigated their potential as doxorubicin sensitizers against a human non-small cell lung cancer A549 cell line that is addicted to Nrf2 via overexpression of p62. KOA153 and the newly synthesized amide compounds exhibited significant doxorubicin-sensitizing activity without cytotoxicity. In addition, dimethylamide derivatives activated Nrf2 in HEK293 cells expressing normal levels of p62. Therefore, dimethylamide derivatives are likely novel type of anticancer agents.