Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/threonine-protein kinase PAK 6 (PAK6)
• Synonyms: EC 2.7.11.1; PAK-5; p21-activated kinase 6; PAK-6
• Gene Name: PAK6
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Prostate cancer
  Schizophrenia
  Squamous cell carcinoma
  Parkinson disease
  Prostate carcinoma
  Prostate neoplasm
• UniProt ID: PAK6_HUMAN
• PDB ID: 2C30; 2ODB; 4KS7; 4KS8; 6QDR; 6QDS
• EC Number: 2.7.11.1
• Pfam ID: PF00786 ; PF00069
• Sequence:
  MFRKKKKKRPEISAPQNFQHRVHTSFDPKEGKFVGLPPQWQNILDTLRRPKPVVDPSRIT
  RVQLQPMKTVVRGSAMPVDGYISGLLNDIQKLSVISSNTLRGRSPTSRRRAQSLGLLGDE
  HWATDPDMYLQSPQSERTDPHGLYLSCNGGTPAGHKQMPWPEPQSPRVLPNGLAAKAQSL
  GPAEFQGASQRCLQLGACLQSSPPGASPPTGTNRHGMKAAKHGSEEARPQSCLVGSATGR
  PGGEGSPSPKTRESSLKRRLFRSMFLSTAATAPPSSSKPGPPPQSKPNSSFRPPQKDNPP
  SLVAKAQSLPSDQPVGTFSPLTTSDTSSPQKSLRTAPATGQLPGRSSPAGSPRTWHAQIS
  TSNLYLPQDPTVAKGALAGEDTGVVTHEQFKAALRMVVDQGDPRLLLDSYVKIGEGSTGI
  VCLAREKHSGRQVAVKMMDLRKQQRRELLFNEVVIMRDYQHFNVVEMYKSYLVGEELWVL
  MEFLQGGALTDIVSQVRLNEEQIATVCEAVLQALAYLHAQGVIHRDIKSDSILLTLDGRV
  KLSDFGFCAQISKDVPKRKSLVGTPYWMAPEVISRSLYATEVDIWSLGIMVIEMVDGEPP
  YFSDSPVQAMKRLRDSPPPKLKNSHKVSPVLRDFLERMLVRDPQERATAQELLDHPFLLQ
  TGLPECLVPLIQLYRKQTSTC
• Function: Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Inhibits also ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD.
• Tissue Specificity: Selectively expressed in brain and testis, with lower levels in multiple tissues including prostate and breast.
• 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)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOH GTPase cycle (R-HSA-9013407)
  RHOV GTPase cycle (R-HSA-9013424)
  Activation of RAC1 (R-HSA-428540)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[6]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[7]
Parkinson disease	DISQVHKL	Limited	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Serine/threonine-protein kinase PAK 6 (PAK6) decreases the response to substance of Afimoxifene.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine/threonine-protein kinase PAK 6 (PAK6).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Serine/threonine-protein kinase PAK 6 (PAK6).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Serine/threonine-protein kinase PAK 6 (PAK6).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Serine/threonine-protein kinase PAK 6 (PAK6).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Serine/threonine-protein kinase PAK 6 (PAK6).	[13]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Serine/threonine-protein kinase PAK 6 (PAK6).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Serine/threonine-protein kinase PAK 6 (PAK6).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase PAK 6 (PAK6).	[17]

References

• [1] Survey of differentially methylated promoters in prostate cancer cell lines.Neoplasia. 2005 Aug;7(8):748-60. doi: 10.1593/neo.05289.
• [2] Increased PAK6 expression in prostate cancer and identification of PAK6 associated proteins.Prostate. 2008 Oct 1;68(14):1510-6. doi: 10.1002/pros.20787.
• [3] MicroRNA-429 inhibits the migration and invasion of colon cancer cells by targeting PAK6/cofilin signaling.Oncol Rep. 2015 Aug;34(2):707-14. doi: 10.3892/or.2015.4039. Epub 2015 Jun 8.
• [4] Expression and prognostic significance of p21-activated kinase 6 in hepatocellular carcinoma.J Surg Res. 2014 Jun 1;189(1):81-8. doi: 10.1016/j.jss.2014.01.049. Epub 2014 Jan 29.
• [5] Downregulation of microRNA-23a suppresses prostate cancer metastasis by targeting the PAK6-LIMK1 signaling pathway.Oncotarget. 2015 Feb 28;6(6):3904-17. doi: 10.18632/oncotarget.2880.
• [6] Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.JAMA Psychiatry. 2019 Oct 1;76(10):1026-1034. doi: 10.1001/jamapsychiatry.2019.1335.
• [7] Distinct DNA methylation profiles between adenocarcinoma and squamous cell carcinoma of human uterine cervix.Oncol Res. 2010;18(9):401-8. doi: 10.3727/096504010x12644422320744.
• [8] Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain.J Neurochem. 2015 Dec;135(6):1242-56. doi: 10.1111/jnc.13369. Epub 2015 Oct 19.
• [9] P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor expression and enhanced matrix metalloproteinase 9 secretion.J Biol Chem. 2013 Feb 1;288(5):3025-35. doi: 10.1074/jbc.M112.424770. Epub 2012 Dec 20.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [14] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] 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.
• [17] 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.
• [18] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.