Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY8JEE4)

• DOT Name: Serine/threonine-protein kinase PAK 4 (PAK4)
• Synonyms: EC 2.7.11.1; p21-activated kinase 4; PAK-4
• Gene Name: PAK4
• UniProt ID: PAK4_HUMAN
• PDB ID: 2BVA ; 2CDZ ; 2J0I ; 2OV2 ; 2Q0N ; 2X4Z ; 4APP ; 4FIE ; 4FIF ; 4FIG ; 4FIH ; 4FII ; 4FIJ ; 4JDH ; 4JDI ; 4JDJ ; 4JDK ; 4L67 ; 4NJD ; 4O0V ; 4O0X ; 4O0Y ; 4XBR ; 4XBU ; 5BMS ; 5I0B ; 5UPK ; 5UPL ; 5VED ; 5VEE ; 5VEF ; 5XVA ; 5XVF ; 5XVG ; 5ZJW ; 6WLX ; 6WLY ; 7CMB ; 7CP3 ; 7CP4 ; 7S46 ; 7S47 ; 7S48 ; 8AHG ; 8AHH ; 8AHI
• EC Number: 2.7.11.1
• Pfam ID: PF00786 ; PF00069
• Sequence:
  MFGKRKKRVEISAPSNFEHRVHTGFDQHEQKFTGLPRQWQSLIEESARRPKPLVDPACIT
  SIQPGAPKTIVRGSKGAKDGALTLLLDEFENMSVTRSNSLRRDSPPPPARARQENGMPEE
  PATTARGGPGKAGSRGRFAGHSEAGGGSGDRRRAGPEKRPKSSREGSGGPQESSRDKRPL
  SGPDVGTPQPAGLASGAKLAAGRPFNTYPRADTDHPSRGAQGEPHDVAPNGPSAGGLAIP
  QSSSSSSRPPTRARGAPSPGVLGPHASEPQLAPPACTPAAPAVPGPPGPRSPQREPQRVS
  HEQFRAALQLVVDPGDPRSYLDNFIKIGEGSTGIVCIATVRSSGKLVAVKKMDLRKQQRR
  ELLFNEVVIMRDYQHENVVEMYNSYLVGDELWVVMEFLEGGALTDIVTHTRMNEEQIAAV
  CLAVLQALSVLHAQGVIHRDIKSDSILLTHDGRVKLSDFGFCAQVSKEVPRRKSLVGTPY
  WMAPELISRLPYGPEVDIWSLGIMVIEMVDGEPPYFNEPPLKAMKMIRDNLPPRLKNLHK
  VSPSLKGFLDRLLVRDPAQRATAAELLKHPFLAKAGPPASIVPLMRQNRTR
• Function: 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. 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.
• Tissue Specificity: Highest expression in prostate, testis and colon.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  T cell receptor sig.ling pathway (hsa04660)
  Regulation of actin cytoskeleton (hsa04810)
  Human immunodeficiency virus 1 infection (hsa05170)
  MicroR.s in cancer (hsa05206)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOH GTPase cycle (R-HSA-9013407)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RHOU GTPase cycle (R-HSA-9013420)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOV GTPase cycle (R-HSA-9013424)
  Activation of RAC1 (R-HSA-428540)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PF-3758309	DM36PKZ	Phase 1	Serine/threonine-protein kinase PAK 4 (PAK4) increases the response to substance of PF-3758309.	[10]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein kinase PAK 4 (PAK4).	[1]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein kinase PAK 4 (PAK4).	[2]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein kinase PAK 4 (PAK4).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase PAK 4 (PAK4).	[6]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Serine/threonine-protein kinase PAK 4 (PAK4).	[8]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Serine/threonine-protein kinase PAK 4 (PAK4).	[9]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of Serine/threonine-protein kinase PAK 4 (PAK4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Serine/threonine-protein kinase PAK 4 (PAK4).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Serine/threonine-protein kinase PAK 4 (PAK4).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein kinase PAK 4 (PAK4).	[7]

References

• [1] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [2] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [3] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [4] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [5] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [6] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [7] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [8] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [9] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [10] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.