Discovery of New Fusobacterium nucleatum Inhibitors to Attenuate Migratory Capability of Colon Cancer Cells by the Drug Repositioning Strategy

Recent studies revealed that intestinal
microbiota played
important
roles in colorectal cancer (CRC) carcinogenesis. Particularly, Fusobacterium nucleatum was confirmed to promote
the proliferation and metastasis of CRC. Therefore, targeting F. nucleatum may be a potential preventive and therapeutic
approach for CRC. Herein, 2,272 off-patent drugs were screened inhibitory
activity against F. nucleatum. Among
the hits, nitisinone was identified as a promising anti-F. nucleatum lead compound. Further optimization
of nitisinone led to the discovery of more potent derivatives. Particularly,
compounds 19q and 22c showed potent anti-F. nucleatum activity (MIC50 = 1 and 2
μg/mL, respectively) with low cytotoxicity. Among them, compound 19q effectively attenuated the migratory ability of MC-38
cells induced by F. nucleatum. Preliminary
mechanism studies suggested that nitisinone and its derivatives might
act by downregulating nitroreductase and tryptophanase. Thus, the
development of small molecule F. nucleatum inhibitors represents an effective strategy to treat CRC.