Target Information
| Target General Information | Top | |||||
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| Target ID |
T98293
(Former ID: TTDI02145)
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| Target Name |
PAK-4 protein kinase (PAK4)
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| Synonyms |
p21-activated kinase 4; Serine/threonine-protein kinase PAK 4; PAK-4; KIAA1142
Click to Show/Hide
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| Gene Name |
PAK4
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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 |
Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN. Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival.
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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 |
MFGKRKKRVEISAPSNFEHRVHTGFDQHEQKFTGLPRQWQSLIEESARRPKPLVDPACIT
SIQPGAPKTIVRGSKGAKDGALTLLLDEFENMSVTRSNSLRRDSPPPPARARQENGMPEE PATTARGGPGKAGSRGRFAGHSEAGGGSGDRRRAGPEKRPKSSREGSGGPQESSRDKRPL SGPDVGTPQPAGLASGAKLAAGRPFNTYPRADTDHPSRGAQGEPHDVAPNGPSAGGLAIP QSSSSSSRPPTRARGAPSPGVLGPHASEPQLAPPACTPAAPAVPGPPGPRSPQREPQRVS HEQFRAALQLVVDPGDPRSYLDNFIKIGEGSTGIVCIATVRSSGKLVAVKKMDLRKQQRR ELLFNEVVIMRDYQHENVVEMYNSYLVGDELWVVMEFLEGGALTDIVTHTRMNEEQIAAV CLAVLQALSVLHAQGVIHRDIKSDSILLTHDGRVKLSDFGFCAQVSKEVPRRKSLVGTPY WMAPELISRLPYGPEVDIWSLGIMVIEMVDGEPPYFNEPPLKAMKMIRDNLPPRLKNLHK VSPSLKGFLDRLLVRDPAQRATAAELLKHPFLAKAGPPASIVPLMRQNRTR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T85C8T | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | KPT-9274 | Drug Info | Phase 1 | Non-hodgkin lymphoma | [2] | |
| 2 | PF-3758309 | Drug Info | Phase 1 | Solid tumour/cancer | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | KPT-9274 | Drug Info | [2] | |||
| 2 | PF-3758309 | 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: PF-3758309 | Ligand Info | |||||
| Structure Description | Crystal Structure of the Human p21-Activated Kinase 4 in Complex with PF-03758309 | PDB:2X4Z | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [1] |
| PDB Sequence |
MSHEQFRAAL
308 QLVVDPGDPR318 SYLDNFIKIG328 EGSTGIVCIA338 TVRSSGKLVA348 VKKMDLRKQQ 358 RRELLFNEVV368 IMRDYQHENV378 VEMYNSYLVG388 DELWVVMEFL398 EGGALTDIVT 408 HTRMNEEQIA418 AVCLAVLQAL428 SVLHAQGVIH438 RDIKSDSILL448 THDGRVKLSD 458 FGFCAQVSKE468 VPRRKLVGTP479 YWMAPELISR489 LPYGPEVDIW499 SLGIMVIEMV 509 DGEPPYFNEP519 PLKAMKMIRD529 NLPPRLKNLH539 KVSPSLKGFL549 DRLLVRDPAQ 559 RATAAELLKH569 PFLAKAGPPA579 SIVPLMRQNR589 T
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ILE327
3.675
GLY328
3.639
GLU329
4.216
GLY330
3.481
SER331
3.825
THR332
3.126
GLY333
3.514
ILE334
4.319
VAL335
3.408
ALA348
3.506
LYS350
3.612
MET352
4.894
VAL379
3.926
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| Ligand Name: AMP-PNP | Ligand Info | |||||
| Structure Description | Crystal structure of Serine/threonine-protein kinase PAK 4 in complex with Paktide S peptide substrate | PDB:4JDI | ||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | No | [3] |
| PDB Sequence |
SHEQFRAALQ
309 LVVDPGDPRS319 YLDNFIKIGE329 GSTGIVCIAT339 VRSSGKLVAV349 KKMDLRKQQR 359 RELLFNEVVI369 MRDYQHENVV379 EMYNSYLVGD389 ELWVVMEFLE399 GGALTDIVTH 409 TRMNEEQIAA419 VCLAVLQALS429 VLHAQGVIHR439 DIKSDSILLT449 HDGRVKLSDF 459 GFCAQVSKEV469 PRRKLVGTPY480 WMAPELISRL490 PYGPEVDIWS500 LGIMVIEMVD 510 GEPPYFNEPP520 LKAMKMIRDN530 LPPRLKNLHK540 VSPSLKGFLD550 RLLVRDPAQR 560 ATAAELLKHP570 FLAKAGPPAS580 IVPLMRQNR
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ILE327
3.562
GLY328
3.717
GLU329
3.991
GLY330
3.391
SER331
2.764
THR332
2.604
GLY333
3.370
VAL335
3.391
ALA348
3.674
LYS350
2.884
GLU366
4.454
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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).
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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| ErbB signaling pathway | hsa04012 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Ras signaling pathway | hsa04014 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Focal adhesion | hsa04510 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| T cell receptor signaling pathway | hsa04660 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Regulation of actin cytoskeleton | hsa04810 | Affiliated Target |
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| Class: Cellular Processes => Cell motility | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 9.21E-05 |
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| Closeness centrality | 2.15E-01 | Radiality | 1.38E+01 | Clustering coefficient | 1.43E-01 |
| Neighborhood connectivity | 3.85E+01 | Topological coefficient | 1.80E-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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| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| 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 | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 8 KEGG Pathways | + | ||||
| 1 | ErbB signaling pathway | |||||
| 2 | Ras signaling pathway | |||||
| 3 | Axon guidance | |||||
| 4 | Focal adhesion | |||||
| 5 | T cell receptor signaling pathway | |||||
| 6 | Regulation of actin cytoskeleton | |||||
| 7 | MicroRNAs in cancer | |||||
| 8 | Renal cell carcinoma | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Cytoskeletal regulation by Rho GTPase | |||||
| 2 | Inflammation mediated by chemokine and cytokine signaling pathway | |||||
| PID Pathway | [+] 3 PID Pathways | + | ||||
| 1 | Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met) | |||||
| 2 | CDC42 signaling events | |||||
| 3 | FGF signaling pathway | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | ErbB Signaling Pathway | |||||
| 2 | Regulation of Actin Cytoskeleton | |||||
| 3 | Focal Adhesion | |||||
| 4 | Integrin-mediated Cell Adhesion | |||||
| References | Top | |||||
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| REF 1 | Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9446-51. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity. Mol Cell. 2014 Jan 9;53(1):140-7. | |||||
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