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 MYCN 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 MYCN expression and partially rescues MI102-mediated MYCN 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.