Target Information
| Target General Information | Top | |||||
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| Target ID |
T13075
(Former ID: TTDI03079)
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| Target Name |
Casein kinase I alpha (CSNK1A1)
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| Synonyms |
Casein kinase I isoform alpha; CKI-alpha; CK1
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| Gene Name |
CSNK1A1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates CTNNB1 at 'Ser-45'. May phosphorylate PER1 and PER2. May play a role in segregating chromosomes during mitosis. May play a role in keratin cytoskeleton disassembly and thereby, it may regulate epithelial cell migration. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.
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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 |
MASSSGSKAEFIVGGKYKLVRKIGSGSFGDIYLAINITNGEEVAVKLESQKARHPQLLYE
SKLYKILQGGVGIPHIRWYGQEKDYNVLVMDLLGPSLEDLFNFCSRRFTMKTVLMLADQM ISRIEYVHTKNFIHRDIKPDNFLMGIGRHCNKLFLIDFGLAKKYRDNRTRQHIPYREDKN LTGTARYASINAHLGIEQSRRDDMESLGYVLMYFNRTSLPWQGLKAATKKQKYEKISEKK MSTPVEVLCKGFPAEFAMYLNYCRGLRFEEAPDYMYLRQLFRILFRTLNHQYDYTFDWTM LKQKAAQQAASSSGQGQQAQTPTGKQTDKTKSNMKGF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | BTX-A51 | Drug Info | Phase 1 | Non-hodgkin lymphoma | [2] | |
| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | D-4476 | Drug Info | Preclinical | Chronic lymphocytic leukaemia | [3] | |
| 2 | IC261 | Drug Info | Preclinical | Pancreatic cancer | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | BTX-A51 | Drug Info | [4] | |||
| 2 | US9096594, 3 | Drug Info | [5] | |||
| 3 | D-4476 | Drug Info | [6] | |||
| 4 | IC261 | Drug Info | [1] | |||
| 5 | PMID24900428C14 | Drug Info | [7] | |||
| 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: S-Lenalidomide | Ligand Info | |||||
| Structure Description | Structural basis of Lenalidomide induced CK1a degradation by the crl4crbn ubiquitin ligase | PDB:5FQD | ||||
| Method | X-ray diffraction | Resolution | 2.45 Å | Mutation | No | [8] |
| PDB Sequence |
EFIVGGKYKL
19 VRKIGSGSFG29 DIYLAINITN39 GEEVAVKLES49 QKARHPQLLY59 ESKLYKILQG 69 GVGIPHIRWY79 GQEKDYNVLV89 MDLLGPSLED99 LFNFCSRRFT109 MKTVLMLADQ 119 MISRIEYVHT129 KNFIHRDIKP139 DNFLMGIGRH149 CNKLFLIDFG159 LAKKYRDNRT 169 RQHIPYREDK179 NLTGTARYAS189 INAHLGIEQS199 RRDDMESLGY209 VLMYFNRTSL 219 PWQGLKAATK229 KQKYEKISEK239 KMSTPVEVLC249 KGFPAEFAMY259 LNYCRGLRFE 269 EAPDYMYLRQ279 LFRILFRTLN289 HQYDYTFDWT299 MLKQ
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| Ligand Name: Casein Kinase inhibitor A86 | Ligand Info | |||||
| Structure Description | Crystal structure of Human CSNK1A1 with A86 | PDB:6GZD | ||||
| Method | X-ray diffraction | Resolution | 2.28 Å | Mutation | No | [9] |
| PDB Sequence |
AEFIVGGKYK
18 LGRKIGSGSF28 GDIYLATNIT38 NGEEVAVKLE48 SQKARHPQLH58 YESKLYKILQ 68 GGVGIPHIRW78 YGQEKDYNVL88 VMDLLGPSLE98 DLFNFCSRRF108 TMKTVLMLAD 118 QMISRIEYVH128 TKNFIHRDIK138 PDNFLMGIGR148 HCNKLFLIDF158 GLAKKYRDNR 168 TRQHIPYRED178 KNLTGTARYA188 SINAHLGIEQ198 SRRDDMESLG208 YVLMYFNRTS 218 LPWQGLKAAT228 KKQKYEKISE238 KKMSTPVEVL248 CKGFPAEFAM258 YLNYCRGLRF 268 EEAPDYMYLR278 QLFRILFRTL288 NHQYDYTFDW298 TMLKQKA
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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).
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 Tissue Distribution
Human Pathway Affiliation
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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Wnt signaling pathway | hsa04310 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Hedgehog signaling pathway | hsa04340 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 14 | Degree centrality | 1.50E-03 | Betweenness centrality | 5.43E-04 |
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| Closeness centrality | 2.47E-01 | Radiality | 1.43E+01 | Clustering coefficient | 3.41E-01 |
| Neighborhood connectivity | 5.91E+01 | Topological coefficient | 1.04E-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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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Crystal structure of a conformation-selective casein kinase-1 inhibitor. J Biol Chem. 2000 Jun 30;275(26):20052-60. | |||||
| REF 2 | ClinicalTrials.gov (NCT04872166) A Study of BTX-A51 in People With Advanced Solid Tumor or Non-Hodgkin Lymphoma. U.S. National Institutes of Health. | |||||
| REF 3 | Circadian rhythm as a therapeutic target. Nat Rev Drug Discov. 2021 Apr;20(4):287-307. | |||||
| REF 4 | Clinical pipeline report, company report or official report of BioTheryX. | |||||
| REF 5 | Kinase inhibitors and methods of use thereof. US9096594. | |||||
| REF 6 | Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization. Eur J Med Chem. 2012 Oct;56:30-8. | |||||
| REF 7 | Structure-Based Design of Potent and Selective CK1gamma Inhibitors. ACS Med Chem Lett. 2012 Oct 18;3(12):1059-64. | |||||
| REF 8 | Structural basis of lenalidomide-induced CK1Alpha degradation by the CRL4(CRBN) ubiquitin ligase. Nature. 2016 Apr 7;532(7597):127-30. | |||||
| REF 9 | Small Molecules Co-targeting CKIAlpha and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25. | |||||
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