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

Authors:

Zhen Tang, Ningjing Zhang, Shuang Chen, Jiebin Fang, Xinyi Tang, Yijie Lou, Yongjun Jiang, Yijun Ma, Xiaoming Chen, Zhe Chen, Shuai Zhan, Xia Ding, Wanjing Ding, Zhongjun Ma

Keywords:

Colorectal Cancer; NOP2/SUN RNA Methyltransferase 3 inhibitor; NSUN3; B19; AMPK-related signaling; STAT3 signaling; antiproliferative; pro-apoptotic

Abstract:

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.

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