6cjy

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Crystal Structure of Mnk2-D228G in complex with Inhibitor

Structural highlights

6cjy is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.05Å
Ligands:F4J, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition.,Reich SH, Sprengeler PA, Chiang GG, Appleman JR, Chen J, Clarine J, Eam B, Ernst JT, Han Q, Goel VK, Han EZR, Huang V, Hung INJ, Jemison A, Jessen KA, Molter J, Murphy D, Neal M, Parker GS, Shaghafi M, Sperry S, Staunton J, Stumpf CR, Thompson PA, Tran C, Webber SE, Wegerski CJ, Zheng H, Webster KR J Med Chem. 2018 Apr 26;61(8):3516-3540. doi: 10.1021/acs.jmedchem.7b01795. Epub , 2018 Mar 29. PMID:29526098[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ Reich SH, Sprengeler PA, Chiang GG, Appleman JR, Chen J, Clarine J, Eam B, Ernst JT, Han Q, Goel VK, Han EZR, Huang V, Hung INJ, Jemison A, Jessen KA, Molter J, Murphy D, Neal M, Parker GS, Shaghafi M, Sperry S, Staunton J, Stumpf CR, Thompson PA, Tran C, Webber SE, Wegerski CJ, Zheng H, Webster KR. Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. J Med Chem. 2018 Apr 26;61(8):3516-3540. doi: 10.1021/acs.jmedchem.7b01795. Epub , 2018 Mar 29. PMID:29526098 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01795

Contents


PDB ID 6cjy

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