Target Information
| Target General Information | Top | |||||
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| Target ID |
T99160
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| Target Name |
MAP kinase signal-integrating kinase 2 (MKNK2)
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| Synonyms |
Mnk2; MAPK signal-integrating kinase 2
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| Gene Name |
MKNK2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| 2 | Colorectal cancer [ICD-11: 2B91] | |||||
| 3 | Liver cancer [ICD-11: 2C12] | |||||
| 4 | Lymphoma [ICD-11: 2A80-2A86] | |||||
| 5 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
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.
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| BioChemical Class |
Protein kinase superfamily. CAMK Ser/Thr protein kinase family
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MVQKKPAELQGFHRSFKGQNPFELAFSLDQPDHGDSDFGLQCSARPDMPASQPIDIPDAK
KRGKKKKRGRATDSFSGRFEDVYQLQEDVLGEGAHARVQTCINLITSQEYAVKIIEKQPG HIRSRVFREVEMLYQCQGHRNVLELIEFFEEEDRFYLVFEKMRGGSILSHIHKRRHFNEL EASVVVQDVASALDFLHNKGIAHRDLKPENILCEHPNQVSPVKICDFDLGSGIKLNGDCS PISTPELLTPCGSAEYMAPEVVEAFSEEASIYDKRCDLWSLGVILYILLSGYPPFVGRCG SDCGWDRGEACPACQNMLFESIQEGKYEFPDKDWAHISCAAKDLISKLLVRDAKQRLSAA QVLQHPWVQGCAPENTLPTPMVLQRNSCAKDLTSFAAEAIAMNRQLAQHDEDLAEEEAAG QGQPVLVRATSRCLQLSPPSQSKLAQRRQRASLSSAPVVLVGDHA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | EFT508 | Drug Info | Phase 2 | Colorectal cancer | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | EFT508 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: EFT508 | Ligand Info | |||||
| Structure Description | Crystal Structure of Mnk2-D228G in complex with Inhibitor | PDB:6CK6 | ||||
| Method | X-ray diffraction | Resolution | 3.32 Å | Mutation | Yes | [2] |
| PDB Sequence |
GSTDSFSGRF
79 EDVYQLQEDV89 LGEGAHARVQ99 TCINLITSQE109 YAVKIIEKQP119 GHIRSRVFRE 129 VEMLYQCQGH139 RNVLELIEFF149 EEEDRFYLVF159 EKMRGGSILS169 HIHKRRHFNE 179 LEASVVVQDV189 ASALDFLHNK199 GIAHRDLKPE209 NILCEHPNQV219 SPVKICDFGG 252 SAEYMAPEVV262 EAFSEEASIY272 DKRCDLWSLG282 VILYILLSGY292 PPFVGRCCGA 310 CPACQNMLFE320 SIQEGKYEFP330 DKDWAHISCA340 AKDLISKLLV350 RDAKQRLSAA 360 QVLQHPWVQG370 C
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LEU90
3.196
GLY91
3.862
GLU92
4.066
GLY93
3.842
ALA96
4.285
VAL98
3.936
ALA111
3.377
LYS113
3.324
GLU129
4.906
LEU143
3.540
PHE159
3.284
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| Ligand Name: Staurosporine | Ligand Info | |||||
| Structure Description | Crystal Structure of Mnk2-D228G in complex with Staurosporine | PDB:2HW7 | ||||
| Method | X-ray diffraction | Resolution | 2.71 Å | Mutation | Yes | [3] |
| PDB Sequence |
GSTDSFSGRF
79 EDVYQLQEDV89 LGEGAHARVQ99 TCINLITSQE109 YAVKIIEKQP119 GHIRSRVFRE 129 VEMLYQCQGH139 RNVLELIEFF149 EEEDRFYLVF159 EKMRGGSILS169 HIHKRRHFNE 179 LEASVVVQDV189 ASALDFLHNK199 GIAHRDLKPE209 NILCEHPNQV219 SPVKICDFGG 252 SAEYMAPEVV262 EAFSEEASIY272 DKRCDLWSLG282 VILYILLSGY292 PPFVGRCCGA 310 CPACQNMLFE320 SIQEGKYEFP330 DKDWAHISCA340 AKDLISKLLV350 RDAKQRLSAA 360 QVLQHPWVQG370 C
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| MAPK signaling pathway | hsa04010 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| HIF-1 signaling pathway | hsa04066 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Insulin signaling pathway | hsa04910 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 7.60E+01 | Topological coefficient | 1.00E+00 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | MAPK signaling pathway | |||||
| 2 | HIF-1 signaling pathway | |||||
| 3 | Insulin signaling pathway | |||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | 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. | |||||
| REF 3 | Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment. EMBO J. 2006 Sep 6;25(17):4020-32. | |||||
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