Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYG2FD1)

• DOT Name: Integrin-linked protein kinase (ILK)
• Synonyms: EC 2.7.11.1; 59 kDa serine/threonine-protein kinase; Beta-integrin-linked kinase; ILK-1; ILK-2; p59ILK
• Gene Name: ILK
• Related Disease: Dilated cardiomyopathy
• UniProt ID: ILK_HUMAN
• PDB ID: 2KBX; 3F6Q; 3IXE; 3KMU; 3KMW; 3REP; 4HI8; 4HI9; 6MIB
• EC Number: 2.7.11.1
• Pfam ID: PF12796 ; PF07714
• Sequence:
  MDDIFTQCREGNAVAVRLWLDNTENDLNQGDDHGFSPLHWACREGRSAVVEMLIMRGARI
  NVMNRGDDTPLHLAASHGHRDIVQKLLQYKADINAVNEHGNVPLHYACFWGQDQVAEDLV
  ANGALVSICNKYGEMPVDKAKAPLRELLRERAEKMGQNLNRIPYKDTFWKGTTRTRPRNG
  TLNKHSGIDFKQLNFLTKLNENHSGELWKGRWQGNDIVVKVLKVRDWSTRKSRDFNEECP
  RLRIFSHPNVLPVLGACQSPPAPHPTLITHWMPYGSLYNVLHEGTNFVVDQSQAVKFALD
  MARGMAFLHTLEPLIPRHALNSRSVMIDEDMTARISMADVKFSFQCPGRMYAPAWVAPEA
  LQKKPEDTNRRSADMWSFAVLLWELVTREVPFADLSNMEIGMKVALEGLRPTIPPGISPH
  VCKLMKICMNEDPAKRPKFDMIVPILEKMQDK
• Function: Receptor-proximal protein kinase regulating integrin-mediated signal transduction. May act as a mediator of inside-out integrin signaling. Focal adhesion protein part of the complex ILK-PINCH. This complex is considered to be one of the convergence points of integrin- and growth factor-signaling pathway. Could be implicated in mediating cell architecture, adhesion to integrin substrates and anchorage-dependent growth in epithelial cells. Regulates cell motility by forming a complex with PARVB. Phosphorylates beta-1 and beta-3 integrin subunit on serine and threonine residues, but also AKT1 and GSK3B.
• Tissue Specificity: Highly expressed in heart followed by skeletal muscle, pancreas and kidney. Weakly expressed in placenta, lung and liver.
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)
  Endometrial cancer (hsa05213)
• Reactome Pathway:
  Cell-extracellular matrix interactions (R-HSA-446353)
  Localization of the PINCH-ILK-PARVIN complex to focal adhesions (R-HSA-446343)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Integrin-linked protein kinase (ILK) affects the response to substance of Gemcitabine.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Integrin-linked protein kinase (ILK).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Integrin-linked protein kinase (ILK).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Integrin-linked protein kinase (ILK).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Integrin-linked protein kinase (ILK).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Integrin-linked protein kinase (ILK).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integrin-linked protein kinase (ILK).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Integrin-linked protein kinase (ILK).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Integrin-linked protein kinase (ILK).	[9]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Integrin-linked protein kinase (ILK).	[10]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Integrin-linked protein kinase (ILK).	[11]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Integrin-linked protein kinase (ILK).	[12]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Integrin-linked protein kinase (ILK).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Integrin-linked protein kinase (ILK).	[3]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Integrin-linked protein kinase (ILK).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Integrin-linked protein kinase (ILK).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Integrin-linked protein kinase (ILK).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Integrin-linked protein kinase (ILK).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [10] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [11] Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis. Oncogene. 2001 Sep 27;20(43):6250-7. doi: 10.1038/sj.onc.1204791.
• [12] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [13] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [14] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [15] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance. Clin Cancer Res. 2005 May 1;11(9):3433-8. doi: 10.1158/1078-0432.CCR-04-1510.