Discovery of SIRT7 Inhibitor as New Therapeutic Options Against Liver Cancer

Optimal therapeutic strategies for liver cancer patients remain challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Emerging evidence has shown that epigenetic factor SIRT7 is involved in various aspects of cancer biology, while inactive SIRT7 reverses human cancer phenotype and suppresses tumor growth. In the present study, we predicted the SIRT7 structure by using the fold recognition (or threading) method and performed structure-based virtual screening to develop specific SIRT7 inhibitor by docking 939319 structurally diverse compounds with SIRT proteins. Compounds with high affinities to SIRT7 but low affinities to other SIRT proteins were chosen as candidates of specific SIRT7 inhibitor. Our leading compounds 2800Z and 40569Z showed strong interaction with SIRT7 protein, and specifically inhibited SIRT7 deacetylation activity in vitro. Our docking results also revealed that ARG-120, TRP-126, and HIS-187 were critical sites responsible for interaction of SIRT7 with small molecules. Mutations in the aforementioned sites significantly abolished interaction and inhibitory effects of compounds to SIRT7. In addition, in vivo data indicated that compounds 2800Z and 40569Z were able to induce apoptosis and increase chemosensitivity to sorafenib in human liver cancer. Our findings demonstrated targeting SIRT7 may offer novel therapeutic options for cancer management, and the value of compounds 2800Z and 40569Z as chemical probes for the study of SIRT7 biological functions as well as starting leads for the development of new therapeutic options against liver cancer.