Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX55OIF)

• DOT Name: Docking protein 6 (DOK6)
• Synonyms: Downstream of tyrosine kinase 6
• Gene Name: DOK6
• Related Disease:
  Osteoporosis
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Hirschsprung disease
  Stomach cancer
  Chronic kidney disease
• UniProt ID: DOK6_HUMAN
• Pfam ID: PF02174 ; PF00169
• Sequence:
  MASNFNDIVKQGYVKIRSRKLGIFRRCWLVFKKASSKGPRRLEKFPDEKAAYFRNFHKVT
  ELHNIKNITRLPRETKKHAVAIIFHDETSKTFACESELEAEEWCKHLCMECLGTRLNDIS
  LGEPDLLAAGVQREQNERFNVYLMPTPNLDIYGECTMQITHENIYLWDIHNAKVKLVMWP
  LSSLRRYGRDSTWFTFESGRMCDTGEGLFTFQTREGEMIYQKVHSATLAIAEQHERLMLE
  MEQKARLQTSLTEPMTLSKSISLPRSAYWHHITRQNSVGEIYSLQGHGFGSSKMSRAQTF
  PSYAPEQSEEAQQPLSRSSSYGFSYSSSLIQ
• Function: DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK6 promotes Ret-mediated neurite growth. May have a role in brain development and/or maintenance.
• Tissue Specificity: Highly expressed in fetal and adult brain. Highly expressed in the cerebellum. Weak expression in kidney, spinal cord and testis.
• Reactome Pathway: RET signaling (R-HSA-8853659)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[2]
Breast cancer	DIS7DPX1	moderate	Biomarker	[2]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[2]
Gastric cancer	DISXGOUK	moderate	Biomarker	[2]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[3]
Stomach cancer	DISKIJSX	moderate	Biomarker	[2]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Docking protein 6 (DOK6).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant affects the methylation of Docking protein 6 (DOK6).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Docking protein 6 (DOK6).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Docking protein 6 (DOK6).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Docking protein 6 (DOK6).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Docking protein 6 (DOK6).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Docking protein 6 (DOK6).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Docking protein 6 (DOK6).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Docking protein 6 (DOK6).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Docking protein 6 (DOK6).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Docking protein 6 (DOK6).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Docking protein 6 (DOK6).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Docking protein 6 (DOK6).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Docking protein 6 (DOK6).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Docking protein 6 (DOK6).	[18]

References

• [1] An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.PLoS Genet. 2010 Jun 10;6(6):e1000977. doi: 10.1371/journal.pgen.1000977.
• [2] DOK6 promoter methylation serves as a potential biomarker affecting prognosis in de novo acute myeloid leukemia.Cancer Med. 2019 Oct;8(14):6393-6402. doi: 10.1002/cam4.2540. Epub 2019 Sep 4.
• [3] Preliminary identification of key miRNAs, signaling pathways, and genes associated with Hirschsprung's disease by analysis of tissue microRNA expression profiles.World J Pediatr. 2017 Oct;13(5):489-495. doi: 10.1007/s12519-017-0064-z. Epub 2017 Sep 30.
• [4] Genetic association for renal traits among participants of African ancestry reveals new loci for renal function.PLoS Genet. 2011 Sep;7(9):e1002264. doi: 10.1371/journal.pgen.1002264. Epub 2011 Sep 8.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17-25. doi: 10.1159/000287353. Epub 2010 Feb 24.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.