| Structural highlights
Function
MKNK2_HUMAN Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
MNK activity is regulated by the p38 and Erk MAPK pathways. Phosphorylation of MNK leads to its activation and binding to the eIF4G/eIF4E complex. MNK then phosphorylates eIF4E at Ser209, whose activation is associated with oncogene translation, leading to tumorigenesis. Given this important role for eIF4E in tumorigenesis, MNK inhibition with novel small molecule inhibitors could be a promising strategy to combat AML, which continues to be an area of unmet medical need. Here, we report the medicinal optimization of a series of novel inhibitors and their evaluation of their effects on eIF4E and leukemia cell viability. We discovered a class of ether-containing compounds with a high MNK1/2 selectivity. These MNK inhibitors show good potency in reducing cell viability and colony formation and have desirable pharmacokinetic properties. X-ray cocrystallization was accomplished to confirm the binding mode of our inhibitors and aid in future optimization.
Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia.,Vagadia PP, Izquierdo-Ferrer J, Mazewski C, Blyth G, Beauchamp EM, Clutter MR, Stern CL, Mishra RK, Nahotko D, Small S, Eckerdt F, Platanias LC, Schiltz GE J Med Chem. 2025 Mar 4. doi: 10.1021/acs.jmedchem.4c03158. PMID:40033556[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. PMID:11154262 doi:10.1128/MCB.21.3.743-754.2001
- ↑ Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol. 2001 Aug;21(16):5500-11. PMID:11463832 doi:http://dx.doi.org/10.1128/MCB.21.16.5500-5511.2001
- ↑ Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC, Han ZG, Proud CG. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Mol Cell Biol. 2003 Aug;23(16):5692-705. PMID:12897141
- ↑ Buxade M, Parra JL, Rousseau S, Shpiro N, Marquez R, Morrice N, Bain J, Espel E, Proud CG. The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. Immunity. 2005 Aug;23(2):177-89. PMID:16111636 doi:http://dx.doi.org/10.1016/j.immuni.2005.06.009
- ↑ Buxade M, Morrice N, Krebs DL, Proud CG. The PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. J Biol Chem. 2008 Jan 4;283(1):57-65. Epub 2007 Oct 26. PMID:17965020 doi:http://dx.doi.org/10.1074/jbc.M705286200
- ↑ Dolniak B, Katsoulidis E, Carayol N, Altman JK, Redig AJ, Tallman MS, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Platanias LC. Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2. J Biol Chem. 2008 May 2;283(18):12034-42. doi: 10.1074/jbc.M708816200. Epub 2008 , Feb 25. PMID:18299328 doi:http://dx.doi.org/10.1074/jbc.M708816200
- ↑ Shveygert M, Kaiser C, Bradrick SS, Gromeier M. Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. Mol Cell Biol. 2010 Nov;30(21):5160-7. doi: 10.1128/MCB.00448-10. Epub 2010 Sep, 7. PMID:20823271 doi:http://dx.doi.org/10.1128/MCB.00448-10
- ↑ Li Y, Yue P, Deng X, Ueda T, Fukunaga R, Khuri FR, Sun SY. Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia. 2010 Oct;12(10):848-55. PMID:20927323
- ↑ Joshi S, Sharma B, Kaur S, Majchrzak B, Ueda T, Fukunaga R, Verma AK, Fish EN, Platanias LC. Essential role for Mnk kinases in type II interferon (IFNgamma) signaling and its suppressive effects on normal hematopoiesis. J Biol Chem. 2011 Feb 25;286(8):6017-26. doi: 10.1074/jbc.M110.197921. Epub 2010 , Dec 13. PMID:21149447 doi:http://dx.doi.org/10.1074/jbc.M110.197921
- ↑ Vagadia PP, Izquierdo-Ferrer J, Mazewski C, Blyth G, Beauchamp EM, Clutter MR, Stern CL, Mishra RK, Nahotko D, Small S, Eckerdt F, Platanias LC, Schiltz GE. Discovery of Potent and Selective MNK Kinase Inhibitors for the Treatment of Leukemia. J Med Chem. 2025 Mar 4. PMID:40033556 doi:10.1021/acs.jmedchem.4c03158
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