Bipyridine Derivatives as NOP2/Sun RNA Methyltransferase 3 Inhibitors for the Treatment of Colorectal Cancer

Based
on the structure of caerulomycin A, 90 novel bipyridine derivatives
were designed and synthesized. Among these, compound B19 exerted strong antitumor effects in vivo and in vitro. Importantly,
NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as
the target specific binding to B19, which inhibits oxidative
phosphorylation of mitochondrial energy metabolism and enhances glycolytic
activity by binding to NSUN3. Knockdown of NSUN3 inhibited
both proliferation and migration of colorectal cancer (CRC) cells
by activating AMPK-related signaling and inhibiting downstream STAT3
signaling to exert antiproliferative and pro-apoptotic effects. Our
findings support the use of NSUN3 inhibitors as promising therapeutic
strategies against CRC.