Target Information
| Target General Information | Top | |||||
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| Target ID |
T71374
(Former ID: TTDI03470)
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| Target Name |
Polo-like kinase 4 (PLK4)
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| Synonyms |
Serine/threonine-protein kinase Sak; Serine/threonine-protein kinase PLK4; Serine/threonine-protein kinase 18; STK18; SAK; PLK-4
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| Gene Name |
PLK4
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| Function |
Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. Required for the recruitment of STIL to the centriole and for STIL-mediated centriole amplification. Serine/threonine-protein kinase that plays a central role in centriole duplication.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.21
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| Sequence |
MATCIGEKIEDFKVGNLLGKGSFAGVYRAESIHTGLEVAIKMIDKKAMYKAGMVQRVQNE
VKIHCQLKHPSILELYNYFEDSNYVYLVLEMCHNGEMNRYLKNRVKPFSENEARHFMHQI ITGMLYLHSHGILHRDLTLSNLLLTRNMNIKIADFGLATQLKMPHEKHYTLCGTPNYISP EIATRSAHGLESDVWSLGCMFYTLLIGRPPFDTDTVKNTLNKVVLADYEMPSFLSIEAKD LIHQLLRRNPADRLSLSSVLDHPFMSRNSSTKSKDLGTVEDSIDSGHATISTAITASSST SISGSLFDKRRLLIGQPLPNKMTVFPKNKSSTDFSSSGDGNSFYTQWGNQETSNSGRGRV IQDAEERPHSRYLRRAYSSDRSGTSNSQSQAKTYTMERCHSAEMLSVSKRSGGGENEERY SPTDNNANIFNFFKEKTSSSSGSFERPDNNQALSNHLCPGKTPFPFADPTPQTETVQQWF GNLQINAHLRKTTEYDSISPNRDFQGHPDLQKDTSKNAWTDTKVKKNSDASDNAHSVKQQ NTMKYMTALHSKPEIIQQECVFGSDPLSEQSKTRGMEPPWGYQNRTLRSITSPLVAHRLK PIRQKTKKAVVSILDSEEVCVELVKEYASQEYVKEVLQISSDGNTITIYYPNGGRGFPLA DRPPSPTDNISRYSFDNLPEKYWRKYQYASRFVQLVRSKSPKITYFTRYAKCILMENSPG ADFEVWFYDGVKIHKTEDFIQVIEKTGKSYTLKSESEVNSLKEEIKMYMDHANEGHRICL ALESIISEEERKTRSAPFFPIIIGRKPGSTSSPKALSPPPSVDSNYPTRERASFNRMVMH SAASPTQAPILNPSMVTNEGLGLTTTASGTDISSNSLKDCLPKSAQLLKSVFVKNVGWAT QLTSGAVWVQFNDGSQLVVQAGVSSISYTSPNGQTTRYGENEKLPDYIKQKLQCLSSILL MFSNPTPNFH 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 | CFI-400945 | Drug Info | Phase 2 | Breast cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | CFI-400945 | Drug Info | [3] | |||
| 2 | XMD8-92 | 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: AMP-PNP | Ligand Info | |||||
| Structure Description | Crystal structure of PLK4 kinase | PDB:3COK | ||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | No | [4] |
| PDB Sequence |
SLATCIGEKI
8 EDFKVGNLLG18 KGSFAGVYRA28 ESIHTGLEVA38 IKMIDKKAMY48 KAGMVQRVQN 58 EVKIHCQLKH68 PSILELYNYF78 EDSNYVYLVL88 EMCHNGEMNR98 YLKNRVKPFS 108 ENEARHFMHQ118 IITGMLYLHS128 HGILHRDLTL138 SNLLLTRNMN148 IKIADFGLAT 158 QLKESDVWSL196 GCMFYTLLIG206 RPPFDTDTVK216 VVLADYEMPS231 FLSIEAKDLI 241 HQLLRRNPAD251 RLSLSSVLDH261 PFMS
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| Ligand Name: Centrinone | Ligand Info | |||||
| Structure Description | Crystal Structure of Plk4 Kinase Domain Bound to Centrinone | PDB:4YUR | ||||
| Method | X-ray diffraction | Resolution | 2.65 Å | Mutation | No | [5] |
| PDB Sequence |
IGEKIEDFKV
14 GNLLGKGSFA24 GVYRAESIHT34 GLEVAIKMID44 KKAMYKAGMV54 QRVQNEVKIH 64 CQLKHPSILE74 LYNYFEDSNY84 VYLVLEMCHN94 GEMNRYLKNR104 VKPFSENEAR 114 HFMHQIITGM124 LYLHSHGILH134 RDLTLSNLLL144 TRNMNIKIAD154 FGLESDVWSL 197 GCMFYTLLIG207 RPPFTVKNTL220 NKVVLADYEM230 PSFLSIEAKD240 LIHQLLRRNP 250 ADRLSLSSVL260 DHPFMS
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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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| FoxO signaling pathway | hsa04068 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 8.46E-04 |
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| Closeness centrality | 2.04E-01 | Radiality | 1.35E+01 | Clustering coefficient | 3.21E-01 |
| Neighborhood connectivity | 1.59E+01 | Topological coefficient | 1.50E-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 | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell. 2010 Sep 14;18(3):258-67. | |||||
| REF 2 | ClinicalTrials.gov (NCT04176848) CFI-400945 and Durvalumab in Patients With Advanced Triple Negative Breast Cancer. U.S. National Institutes of Health. | |||||
| REF 3 | Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell. 2014 Aug 11;26(2):163-76. | |||||
| REF 4 | Crystal structure of PLK4 kinase. | |||||
| REF 5 | Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science. 2015 Jun 5;348(6239):1155-60. | |||||
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