Target Information
| Target General Information | Top | |||||
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| Target ID |
T00852
(Former ID: TTDI01377)
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| Target Name |
Serine/threonine-protein kinase cot (COT)
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| Synonyms |
Tumor progression locus 2; TPL-2; Proto-oncogene c-Cot; Mitogen-activated protein kinase kinase kinase 8; ESTF; Cancer Osaka thyroid oncogene; COT
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| Gene Name |
MAP3K8
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Indeterminate colitis [ICD-11: DD72] | |||||
| Function |
Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.25
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| Sequence |
MEYMSTGSDNKEEIDLLIKHLNVSDVIDIMENLYASEEPAVYEPSLMTMCQDSNQNDERS
KSLLLSGQEVPWLSSVRYGTVEDLLAFANHISNTAKHFYGQRPQESGILLNMVITPQNGR YQIDSDVLLIPWKLTYRNIGSDFIPRGAFGKVYLAQDIKTKKRMACKLIPVDQFKPSDVE IQACFRHENIAELYGAVLWGETVHLFMEAGEGGSVLEKLESCGPMREFEIIWVTKHVLKG LDFLHSKKVIHHDIKPSNIVFMSTKAVLVDFGLSVQMTEDVYFPKDLRGTEIYMSPEVIL CRGHSTKADIYSLGATLIHMQTGTPPWVKRYPRSAYPSYLYIIHKQAPPLEDIADDCSPG MRELIEASLERNPNHRPRAADLLKHEALNPPREDQPRCQSLDSALLERKRLLSRKELELP ENIADSSCTGSTEESEMLKRQRSLYIDLGALAGYFNLVRGPPTLEYG 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 | GS-5290 | Drug Info | Phase 1 | Inflammatory bowel disease | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | GS-5290 | Drug Info | [2] | |||
| 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: 5-[5-(1h-Indol-3-Yl)-1h-Pyrrolo[2,3-B]pyridin-3-Yl]-1,3,4-Oxadiazol-2-Amine | Ligand Info | |||||
| Structure Description | Crystal structure of COT kinase domain in complex with 5-(5-(1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3,4-oxadiazol-2-amine | PDB:4Y85 | ||||
| Method | X-ray diffraction | Resolution | 2.33 Å | Mutation | No | [3] |
| PDB Sequence |
LSSVRYGTVE
82 DLLAFANHIS92 NTPQESGILL110 NMVITPQNGR120 YQIDSDVLLI130 PWKLTYRNIF 143 IPRGAFGKVY153 LAQDIKTKKR163 MACKLIPVDQ173 FKPSDVEIQA183 CFRHENIAEL 193 YGAVLWGETV203 HLFMEAGEGG213 SVLEKLESCG223 PMREFEIIWV233 TKHVLKGLDF 243 LHSKKVIHHD253 IKPSNIVFMS263 TKAVLVDFGL273 SVQMTEDVYF283 PKDLRGTEIY 293 MSPEVILCRG303 HSTKADIYSL313 GATLIHMQTG323 TPPWVKRYPR333 SAYPSYLYII 343 HKQAPPLEDI353 ADDCSPGMRE363 LIEASLERNP373 NHRPRAADLL383 KHEALNP |
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TRP132
3.489
PHE143
3.795
PRO145
3.370
ARG146
4.751
GLY147
3.381
ALA148
4.848
VAL152
3.410
ALA165
3.253
LYS167
2.885
ALA191
4.671
MET207
3.725
GLU208
2.809
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| Ligand Name: N-[2-(Morpholin-4-Yl)ethyl]-6-(8-Phenyl-1h-Imidazo[4,5-C][1,7]naphthyridin-1-Yl)-1,3-Benzothiazol-2-Amine | Ligand Info | |||||
| Structure Description | Discovery of imidazoquinolines as a novel class of potent, selective and in vivo efficacious COT kinase inhibitors | PDB:5IU2 | ||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [4] |
| PDB Sequence |
LSSVRYGTVE
82 DLLAFANHIS92 NFYGQRPQES106 GILLNMVITP116 QNGRYQIDSD126 VLLIPWKLTY 136 RNGSDFIPRG147 AFGKVYLAQD157 IKTKKRMACK167 LIPVDQFKPS177 DVEIQACFRH 187 ENIAELYGAV197 LWGETVHLFM207 EAGEGGSVLE217 KLESCGPMRE227 FEIIWVTKHV 237 LKGLDFLHSK247 KVIHHDIKPS257 NIVFMSTKAV267 LVDFGLSVQM277 TEDVYFPKDL 287 RGTEIYMSPE297 VILCRGHSTK307 ADIYSLGATL317 IHMQTGTPPW327 VKRYPRSAYP 337 SYLYIIHKQA347 PPLEDIADDC357 SPGMRELIEA367 SLERNPNHRP377 RAADLLKHEA 387 LN
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TRP132
3.389
LYS133
4.946
LEU134
3.531
TYR136
4.527
PRO145
4.311
ALA148
4.157
PHE149
3.250
GLY150
3.383
LYS151
4.427
VAL152
3.560
ALA165
3.433
LYS167
3.565
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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 | ||
| Toll-like receptor signaling pathway | hsa04620 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| T cell receptor signaling pathway | hsa04660 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| TNF signaling pathway | hsa04668 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 1.42E-06 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 1.67E-01 |
| Neighborhood connectivity | 2.20E+01 | Topological coefficient | 2.99E-01 | 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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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | Cot/Tpl-2 protein kinase as a target for the treatment of inflammatory disease. Curr Top Med Chem. 2009;9(7):611-22. | |||||
| REF 2 | Clinical pipeline report, company report or official report of Gilead | |||||
| REF 3 | The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold. J Biol Chem. 2015 Jun 12;290(24):15210-8. | |||||
| REF 4 | Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors. J Med Chem. 2016 Aug 25;59(16):7544-60. | |||||
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