Target Information
| Target General Information | Top | |||||
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| Target ID |
T08326
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| Target Name |
Cyclin-dependent kinase 12 (CDK12)
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| Synonyms |
Cdc2-related kinase, arginine/serine-rich; CrkRS; Cell division cycle 2-related protein kinase 7; CDC2-related protein kinase 7; Cell division protein kinase 12; hCDK12
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| Gene Name |
CDK12
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Leishmaniasis [ICD-11: 1F54] | |||||
| Function |
Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.22
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| Sequence |
MPNSERHGGKKDGSGGASGTLQPSSGGGSSNSRERHRLVSKHKRHKSKHSKDMGLVTPEA
ASLGTVIKPLVEYDDISSDSDTFSDDMAFKLDRRENDERRGSDRSDRLHKHRHHQHRRSR DLLKAKQTEKEKSQEVSSKSGSMKDRISGSSKRSNEETDDYGKAQVAKSSSKESRSSKLH KEKTRKERELKSGHKDRSKSHRKRETPKSYKTVDSPKRRSRSPHRKWSDSSKQDDSPSGA SYGQDYDLSPSRSHTSSNYDSYKKSPGSTSRRQSVSPPYKEPSAYQSSTRSPSPYSRRQR SVSPYSRRRSSSYERSGSYSGRSPSPYGRRRSSSPFLSKRSLSRSPLPSRKSMKSRSRSP AYSRHSSSHSKKKRSSSRSRHSSISPVRLPLNSSLGAELSRKKKERAAAAAAAKMDGKES KGSPVFLPRKENSSVEAKDSGLESKKLPRSVKLEKSAPDTELVNVTHLNTEVKNSSDTGK VKLDENSEKHLVKDLKAQGTRDSKPIALKEEIVTPKETETSEKETPPPLPTIASPPPPLP TTTPPPQTPPLPPLPPIPALPQQPPLPPSQPAFSQVPASSTSTLPPSTHSKTSAVSSQAN SQPPVQVSVKTQVSVTAAIPHLKTSTLPPLPLPPLLPGDDDMDSPKETLPSKPVKKEKEQ RTRHLLTDLPLPPELPGGDLSPPDSPEPKAITPPQQPYKKRPKICCPRYGERRQTESDWG KRCVDKFDIIGIIGEGTYGQVYKAKDKDTGELVALKKVRLDNEKEGFPITAIREIKILRQ LIHRSVVNMKEIVTDKQDALDFKKDKGAFYLVFEYMDHDLMGLLESGLVHFSEDHIKSFM KQLMEGLEYCHKKNFLHRDIKCSNILLNNSGQIKLADFGLARLYNSEESRPYTNKVITLW YRPPELLLGEERYTPAIDVWSCGCILGELFTKKPIFQANLELAQLELISRLCGSPCPAVW PDVIKLPYFNTMKPKKQYRRRLREEFSFIPSAALDLLDHMLTLDPSKRCTAEQTLQSDFL KDVELSKMAPPDLPHWQDCHELWSKKRRRQRQSGVVVEEPPPSKTSRKETTSGTSTEPVK NSSPAPPQPAPGKVESGAGDAIGLADITQQLNQSELAVLLNLLQSQTDLSIPQMAQLLNI HSNPEMQQQLEALNQSISALTEATSQQQDSETMAPEESLKEAPSAPVILPSAEQTTLEAS STPADMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTPTMPQEEAAACPPHIL PPEKRPPEPPGPPPPPPPPPLVEGDLSSAPQELNPAVTAALLQLLSQPEAEPPGHLPHEH QALRPMEYSTRPRPNRTYGNTDGPETGFSAIDTDERNSGPALTESLVQTLVKNRTFSGSL SHLGESSSYQGTGSVQFPGDQDLRFARVPLALHPVVGQPFLKAEGSSNSVVHAETKLQNY GELGPGTTGASSSGAGLHWGGPTQSSAYGKLYRGPTRVPPRGGRGRGVPY 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 | GSK3186899 | Drug Info | Phase 1 | Leishmaniasis | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | GSK3186899 | Drug Info | [1] | |||
| 2 | THZ531 | 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: adenosine diphosphate | Ligand Info | |||||
| Structure Description | Crystal structure of human Cdk12/Cyclin K in complex with ADP-aluminum fluoride | PDB:4NST | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [4] |
| PDB Sequence |
ESDWGKRCVD
725 KFDIIGIIGE735 GTYGQVYKAK745 DKDTGELVAL755 KKVRLDNEKE765 GFPITAIREI 775 KILRQLIHRS785 VVNMKEIVTD795 KQDGAFYLVF813 EYMDHDLMGL823 LESGLVHFSE 833 DHIKSFMKQL843 MEGLEYCHKK853 NFLHRDIKCS863 NILLNNSGQI873 KLADFGLARL 883 YNSEESRPYN894 KVITLWYRPP904 ELLLGEERYT914 PAIDVWSCGC924 ILGELFTKKP 934 IFQANLELAQ944 LELISRLCGS954 PCPAVWPDVI964 KLPYFNTMKP974 KKQYRRRLRE 984 EFSFIPSAAL994 DLLDHMLTLD1004 PSKRCTAEQT1014 LQSDFLKDVE1024 LSKMAPPDLP 1034 HWQDCHELWS1044 KK
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ILE733
3.461
GLY734
4.155
GLU735
3.234
GLY736
2.961
THR737
2.914
VAL741
3.881
ALA754
3.255
LYS756
2.791
GLU774
4.822
VAL787
4.458
PHE813
3.304
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| Ligand Name: Phosphonothreonine | Ligand Info | |||||
| Structure Description | Crystal structure of human Cdk12/Cyclin K in complex with ADP-aluminum fluoride | PDB:4NST | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [4] |
| PDB Sequence |
ESDWGKRCVD
725 KFDIIGIIGE735 GTYGQVYKAK745 DKDTGELVAL755 KKVRLDNEKE765 GFPITAIREI 775 KILRQLIHRS785 VVNMKEIVTD795 KQDGAFYLVF813 EYMDHDLMGL823 LESGLVHFSE 833 DHIKSFMKQL843 MEGLEYCHKK853 NFLHRDIKCS863 NILLNNSGQI873 KLADFGLARL 883 YNSEESRPYN894 KVITLWYRPP904 ELLLGEERYT914 PAIDVWSCGC924 ILGELFTKKP 934 IFQANLELAQ944 LELISRLCGS954 PCPAVWPDVI964 KLPYFNTMKP974 KKQYRRRLRE 984 EFSFIPSAAL994 DLLDHMLTLD1004 PSKRCTAEQT1014 LQSDFLKDVE1024 LSKMAPPDLP 1034 HWQDCHELWS1044 KK
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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 | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 2.23E-08 |
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| Closeness centrality | 1.91E-01 | Radiality | 1.32E+01 | Clustering coefficient | 6.67E-01 |
| Neighborhood connectivity | 3.60E+01 | Topological coefficient | 5.00E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of GlaxoSmithKline. | |||||
| REF 2 | ClinicalTrials.gov (NCT03874234) Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects. U.S. National Institutes of Health. | |||||
| REF 3 | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016 Oct;12(10):876-84. | |||||
| REF 4 | The structure and substrate specificity of human Cdk12/Cyclin K. Nat Commun. 2014 Mar 24;5:3505. | |||||
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