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

Abstract

Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound <b>B19</b> 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 <b>B19</b>, which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of <i>NSUN3</i> 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.