Target Information
| Target General Information | Top | |||||
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| Target ID |
T90553
(Former ID: TTDC00281)
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| Target Name |
Microtubule affinity regulating kinase 3 (MARK3)
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| Synonyms |
cTAK1; Serine/threonine-protein kinase p78; Ser/Thr protein kinase PAR-1; Protein kinase STK10); Protein kinase STK10; Par-1a; MAP/microtubule affinity-regulating kinase 3; EMK2; EMK-2; ELKL motif kinase 2; Cdc25C-associated protein kinase 1; C-TAK1
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| Gene Name |
MARK3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Peritoneal cancer [ICD-11: 2C51] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Involved in the specific phosphorylation of microtubule-associated proteins for MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU. Phosphorylates CDC25C on 'Ser-216'. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Negatively regulates the Hippo signaling pathway and antagonizes the phosphorylation of LATS1. Cooperates with DLG5 to inhibit the kinase activity of STK3/MST2 toward LATS1. Serine/threonine-protein kinase.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MSTRTPLPTVNERDTENHTSHGDGRQEVTSRTSRSGARCRNSIASCADEQPHIGNYRLLK
TIGKGNFAKVKLARHILTGREVAIKIIDKTQLNPTSLQKLFREVRIMKILNHPNIVKLFE VIETEKTLYLIMEYASGGEVFDYLVAHGRMKEKEARSKFRQIVSAVQYCHQKRIVHRDLK AENLLLDADMNIKIADFGFSNEFTVGGKLDTFCGSPPYAAPELFQGKKYDGPEVDVWSLG VILYTLVSGSLPFDGQNLKELRERVLRGKYRIPFYMSTDCENLLKRFLVLNPIKRGTLEQ IMKDRWINAGHEEDELKPFVEPELDISDQKRIDIMVGMGYSQEEIQESLSKMKYDEITAT YLLLGRKSSELDASDSSSSSNLSLAKVRPSSDLNNSTGQSPHHKVQRSVSSSQKQRRYSD HAGPAIPSVVAYPKRSQTSTADSDLKEDGISSRKSSGSAVGGKGIAPASPMLGNASNPNK ADIPERKKSSTVPSSNTASGGMTRRNTYVCSERTTADRHSVIQNGKENSTIPDQRTPVAS THSISSAATPDRIRFPRGTASRSTFHGQPRERRTATYNGPPASPSLSHEATPLSQTRSRG STNLFSKLTSKLTRRNMSFRFIKRLPTEYERNGRYEGSSRNVSAEQKDENKEAKPRSLRF TWSMKTTSSMDPGDMMREIRKVLDANNCDYEQRERFLLFCVHGDGHAENLVQWEMEVCKL PRLSLNGVRFKRISGTSIAFKNIASKIANELKL 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 | CBP-501 | Drug Info | Phase 1/2 | Mesothelioma | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | CBP-501 | Drug Info | [1] | |||
| 2 | PMID23099093C17d | Drug Info | [3] | |||
| 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-bromo-4-N-[2-(1H-imidazol-5-yl)ethyl]-2-N-[3-(morpholin-4-ylmethyl)phenyl]pyrimidine-2,4-diamine | Ligand Info | |||||
| Structure Description | The MARK3 Kinase Domain Bound To AA-CS-1-008 | PDB:7P1L | ||||
| Method | X-ray diffraction | Resolution | 1.95 Å | Mutation | No | [4] |
| PDB Sequence |
QPHIGNYRLL
59 KTIGKGNFAK69 VKLARHILTG79 REVAIKIIDK89 TQLNPTSLQK99 LFREVRIMKI 109 LNHPNIVKLF119 EVIETEKTLY129 LIMEYASGGE139 VFDYLVAHGR149 MKEKEARSKF 159 RQIVSAVQYC169 HQKRIVHRDL179 KAENLLLDAD189 MNIKIADFGF199 SNEFTVSPPY 218 AAPELDGPEV234 DVWSLGVILY244 TLVSGSLPFD254 GQNLKELRER264 VLRGKYRIPF 274 YMSTDCENLL284 KRFLVLNPIK294 RGTLEQIMKD304 RWINAGHEED314 ELKPFVEPEL 324 DISDQKRIDI334 MVGMGYSQEE344 IQESLSKMKY354 DEITATYLLL364 G |
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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 Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
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 Tissue Distribution
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 2.09E-07 |
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| Closeness centrality | 1.96E-01 | Radiality | 1.34E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.10E+01 | Topological coefficient | 5.56E-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 Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | RAF activation | |||||
| 2 | MAP2K and MAPK activation | |||||
| 3 | Negative regulation of MAPK pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | National Cancer Institute Drug Dictionary (drug id 577812). | |||||
| REF 2 | ClinicalTrials.gov (NCT00700336) Study of CBP501 + Pemetrexed + Cisplatin on MPM (Phase I/II). U.S. National Institutes of Health. | |||||
| REF 3 | Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKepsilon kinases. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7169-73. | |||||
| REF 4 | Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration. J Med Chem. 2022 Jan 27;65(2):1313-1328. | |||||
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