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Updated: Jan 19, 2026
02:34
Inhibition of CDK Activity
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MLN4924: additional activities beyond neddylation inhibition
Qiyin Zhou1,2, Yi Sun1,3
1Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Molecular & Cellular Oncology
|September 19, 2019
Summary
MLN4924, a NAE inhibitor, unexpectedly activates EGFR and PI3K/AKT1 signaling, promoting tumor growth and glycolysis by inhibiting ciliogenesis and triggering PKM2 tetramerization.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- MLN4924 is a known inhibitor of NEDD8 activating enzyme (NAE).
- NAE inhibition blocks cullin neddylation, inactivating cullin-RING ligases.
- The precise downstream effects of MLN4924 beyond NAE inhibition are not fully understood.
Purpose of the Study:
- To investigate the additional molecular activities of MLN4924.
- To elucidate the signaling pathways affected by MLN4924.
- To understand the impact of MLN4924 on cancer cell phenotypes like tumor sphere formation and glycolysis.
Main Methods:
- Utilized MLN4924 as a small molecular inhibitor.
- Assessed EGFR dimerization and downstream signaling (RAS/MAPK, PI3K/AKT1).
- Monitored ciliogenesis and PKM2 (pyruvate kinase M2) tetramerization.
Main Results:
- MLN4924 triggered EGFR dimerization and activated RAS/MAPK and PI3K/AKT1 pathways.
- MLN4924 treatment stimulated tumor sphere formation and inhibited ciliogenesis.
- MLN4924 induced PKM2 tetramerization, promoting glycolysis.
Conclusions:
- MLN4924 exhibits pleiotropic effects beyond NAE inhibition.
- The drug activates oncogenic signaling pathways and promotes cancer cell phenotypes.
- MLN4924's impact on glycolysis and ciliogenesis suggests novel therapeutic implications.
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