1. Bipyridine Derivatives as NOP2/Sun RNA Methyltransferase 3 Inhibitors for the Treatment of Colorectal Cancer.
- Author
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Tang Z, Zhang N, Chen S, Fang J, Tang X, Lou Y, Jiang Y, Ma Y, Chen X, Chen Z, Zhan S, Ding X, Ding W, and Ma Z
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Methyltransferases antagonists & inhibitors, Methyltransferases metabolism, Apoptosis drug effects, Pyridines pharmacology, Pyridines chemistry, Pyridines chemical synthesis, Mice, Nude, Structure-Activity Relationship, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors therapeutic use, Mice, Inbred BALB C, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor metabolism, Cell Movement drug effects, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Colorectal Neoplasms metabolism, Cell Proliferation drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents therapeutic use
- 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.
- Published
- 2024
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