Novel Atg4B inhibitors potentiate cisplatin therapy in lung cancer cells through blockade of autophagy

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Autophagy induction in tumors is implicated in tumor malignancy and acquisition of anticancer-drug resistance, and hence, autophagy inhibitors are expected as novel anticancer agents. Atg4B, a cysteine proteinase, is a key enzyme in autophagy process, and considered as one of desirable targets for development of selective autophagy inhibitors. In this study, to search novel inhibitors of Atg4B, we employed the virtual screening approach and differential scanning fluorimetry analysis, and found two compounds 1 (2-methyl-5-oxo-5H-[1,3,4]thiadiazolo-[3,2-a]pyrimidine-6-carboxylic acid) and 17 (methyl 4-({2-[(4,6-diaminopyrimidin-2-yl)sulfanyl]propanoyl} amino)benzoate), showing IC50 values of 10 and 12 µM, respectively, in in vitro LC3 cleavage assay of Atg4B. Molecular docking analysis suggested that 1 and 17 bind to the catalytic domain of Atg4B. The treatments with 1 and 17 significantly suppressed autophagy induction to lung cancer A549 cells by tamoxifen and cisplatin, in which their cotreatments promoted tamoxifen- and cisplatin-induced apoptotic cell death. Moreover, the autophagy suppression by 1 and 17 remarkably restored the sensitivity to cisplatin in cisplatin-resistant A549 cells. Thus, 1 and 17 represent promising leads for future development of potent and selective Atg4B inhibitors that augment existing chemotherapy efficacy.