Chemical Screening of RIKEN Natural Products Depository Identified a MYCN Expression Inhibitor Partially through HGF–MET Signaling Pathway

The oncogene MYCN is predominantly expressed in cancer stem-like cells, where it drives tumor growth, metastasis, and therapeutic resistance in hepatocellular carcinoma (HCC). In this study, we explored MYCN Inhibitors (MI) from the RIKEN Natural Products Depository chemical library and identified NPD15261 (designated as MI102) as a selective small-molecule inhibitor of <i>MYCN</i> expression. MI102 markedly reduced MYCN mRNA and protein levels in HCC cells, suppressing proliferation and colony formation, while inducing apoptosis, with minimal impact on normal hepatic cells. Mechanistically, kinase profiling revealed that MI102 is a highly selective inhibitor of MET receptor tyrosine kinase that specifically blocks phosphorylation at Y1234/Y1235. Hepatocyte growth factor-mediated MET activation induces <i>MYCN</i> expression and partially rescues MI102-mediated <i>MYCN</i> suppression. Notably, MI102 effect exhibited superior tumor cell selectivity compared with the MET inhibitor tivantinib. At the transcriptional level, RNA-seq revealed that MI102 globally downregulated MYCN-associated oncogenic programs. Collectively, these findings establish pharmacological downregulation of MYCN as a promising therapeutic strategy for HCC and reveal a functional link between MET signaling and MYCN-driven oncogenic pathways.