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Bipyridine Derivatives as NOP2/Sun RNA Methyltransferase 3 Inhibitors for the Treatment of Colorectal Cancer.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Aug 08; Vol. 67 (15), pp. 13446-13473. Date of Electronic Publication: 2024 Jul 25. - Publication Year :
- 2024
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39054645
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c01323