Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH3XY8B)

• DOT Name: Dedicator of cytokinesis protein 4 (DOCK4)
• Gene Name: DOCK4
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Autism spectrum disorder
  Bipolar disorder
  Bone osteosarcoma
  Carcinoma
  Lung adenocarcinoma
  Major depressive disorder
  Myelodysplastic syndrome
  Neuroblastoma
  Non-insulin dependent diabetes
  Osteosarcoma
  Ovarian cancer
  Pancytopenia
  Neoplasm
  Schizophrenia
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Glioblastoma multiforme
• UniProt ID: DOCK4_HUMAN
• Pfam ID: PF06920 ; PF20422 ; PF20421 ; PF14429 ; PF16172 ; PF07653
• Sequence:
  MWIPTEHEKYGVVIASFRGTVPYGLSLEIGDTVQILEKCDGWYRGFALKNPNIKGIFPSS
  YVHLKNACVKNKGQFEMVIPTEDSVITEMTSTLRDWGTMWKQLYVRNEGDLFHRLWHIMN
  EILDLRRQVLVGHLTHDRMKDVKRHITARLDWGNEQLGLDLVPRKEYAMVDPEDISITEL
  YRLMEHRHRKKDTPVQASSHHLFVQMKSLMCSNLGEELEVIFSLFDSKENRPISERFFLR
  LNRNGLPKAPDKPERHCSLFVDLGSSELRKDIYITVHIIRIGRMGAGEKKNACSVQYRRP
  FGCAVLSIADLLTGETKDDLILKVYMCNTESEWYQIHENIIKKLNARYNLTGSNAGLAVS
  LQLLHGDIEQIRREYSSVFSHGVSITRKLGFSNIIMPGEMRNDLYITIERGEFEKGGKSV
  ARNVEVTMFIVDSSGQTLKDFISFGSGEPPASEYHSFVLYHNNSPRWSELLKLPIPVDKF
  RGAHIRFEFRHCSTKEKGEKKLFGFSFVPLMQEDGRTLPDGTHELIVHKCEENTNLQDTT
  RYLKLPFSKGIFLGNNNQAMKATKESFCITSFLCSTKLTQNGDMLDLLKWRTHPDKITGC
  LSKLKEIDGSEIVKFLQDTLDTLFGILDENSQKYGSKVFDSLVHIINLLQDSKFHHFKPV
  MDTYIESHFAGALAYRDLIKVLKWYVDRITEAERQEHIQEVLKAQEYIFKYIVQSRRLFS
  LATGGQNEEEFRCCIQELLMSVRFFLSQESKGSGALSQSQAVFLSSFPAVYSELLKLFDV
  REVANLVQDTLGSLPTILHVDDSLQAIKLQCIGKTVESQLYTNPDSRYILLPVVLHHLHI
  HLQEQKDLIMCARILSNVFCLIKKNSSEKSVLEEIDVIVASLLDILLRTILEITSRPQPS
  SSAMRFQFQDVTGEFVACLLSLLRQMTDRHYQQLLDSFNTKEELRDFLLQIFTVFRILIR
  PEMFPKDWTVMRLVANNVIITTVLYLSDALRKNFLNENFDYKIWDSYFYLAVIFINQLCL
  QLEMFTPSKKKKVLEKYGDMRVTMGCEIFSMWQNLGEHKLHFIPALIGPFLEVTLIPQPD
  LRNVMIPIFHDMMDWEQRRSGNFKQVEAKLIDKLDSLMSEGKGDETYRELFNSILLKKIE
  RETWRESGVSLIATVTRLMERLLDYRDCMKMGEVDGKKIGCTVSLLNFYKTELNKEEMYI
  RYIHKLYDLHLKAQNFTEAAYTLLLYDELLEWSDRPLREFLTYPMQTEWQRKEHLHLTII
  QNFDRGKCWENGIILCRKIAEQYESYYDYRNLSKMRMMEASLYDKIMDQQRLEPEFFRVG
  FYGKKFPFFLRNKEFVCRGHDYERLEAFQQRMLNEFPHAIAMQHANQPDETIFQAEAQYL
  QIYAVTPIPESQEVLQREGVPDNIKSFYKVNHIWKFRYDRPFHKGTKDKENEFKSLWVER
  TSLYLVQSLPGISRWFEVEKREVVEMSPLENAIEVLENKNQQLKTLISQCQTRQMQNINP
  LTMCLNGVIDAAVNGGVSRYQEAFFVKEYILSHPEDGEKIARLRELMLEQAQILEFGLAV
  HEKFVPQDMRPLHKKLVDQFFVMKSSLGIQEFSACMQASPVHFPNGSPRVCRNSAPASVS
  PDGTRVIPRRSPLSYPAVNRYSSSSLSSQASAEVSNITGQSESSDEVFNMQPSPSTSSLS
  STHSASPNVTSSAPSSARASPLLSDKHKHSRENSCLSPRERPCSAIYPTPVEPSQRMLFN
  HIGDGALPRSDPNLSAPEKAVNPTPSSWSLDSGKEAKNMSDSGKLISPPVPPRPTQTASP
  ARHTTSVSPSPAGRSPLKGSVQSFTPSPVEYHSPGLISNSPVLSGSYSSGISSLSRCSTS
  ETSGFENQVNEQSAPLPVPVPVPVPSYGGEEPVRKESKTPPPYSVYERTLRRPVPLPHSL
  SIPVTSEPPALPPKPLAARSSHLENGARRTDPGPRPRPLPRKVSQL
• Function: Functions as a guanine nucleotide exchange factor (GEF) that promotes the exchange of GDP to GTP, converting inactive GDP-bound small GTPases into their active GTP-bound form. Involved in regulation of adherens junction between cells. Plays a role in cell migration ; [Isoform 2]: Has a higher guanine nucleotide exchange factor activity compared to other isoforms.
• Tissue Specificity: Widely expressed at low level. Highly expressed in skeletal muscle, prostate and ovary.; [Isoform 2]: May be specifically expressed in the brain and eye.
• KEGG Pathway: Rap1 sig.ling pathway (hsa04015)
• Reactome Pathway:
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[8]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[10]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[2]
Pancytopenia	DISVKEHV	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[5]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[12]
Breast cancer	DIS7DPX1	Limited	Biomarker	[13]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[14]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[21]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[23]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[29]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Dedicator of cytokinesis protein 4 (DOCK4).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Dedicator of cytokinesis protein 4 (DOCK4).	[26]

References

• [1] DOCK4 deletion at 7q31.1 in a de novo acute myeloid leukemia with a normal karyotype.Cell Oncol (Dordr). 2013 Oct;36(5):395-403. doi: 10.1007/s13402-013-0145-5. Epub 2013 Aug 27.
• [2] DOCK4, a GTPase activator, is disrupted during tumorigenesis.Cell. 2003 Mar 7;112(5):673-84. doi: 10.1016/s0092-8674(03)00155-7.
• [3] SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis.Nature. 2019 May;569(7757):565-569. doi: 10.1038/s41586-019-1140-4. Epub 2019 Apr 24.
• [4] Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function.Mol Psychiatry. 2021 May;26(5):1505-1519. doi: 10.1038/s41380-019-0472-7. Epub 2019 Aug 6.
• [5] Genome-wide association study identifies common variants associated with pharmacokinetics of psychotropic drugs.J Psychopharmacol. 2015 Aug;29(8):884-91. doi: 10.1177/0269881115584469. Epub 2015 May 5.
• [6] Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-grade and high-grade carcinomas.Cancer Res. 2009 May 1;69(9):4036-42. doi: 10.1158/0008-5472.CAN-08-3913. Epub 2009 Apr 21.
• [7] TGF-/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis.Genes Dev. 2015 Feb 1;29(3):250-61. doi: 10.1101/gad.248963.114.
• [8] Loss of Function of DOCK4 in Myelodysplastic Syndromes Stem Cells is Restored by Inhibitors of DOCK4 Signaling Networks.Clin Cancer Res. 2019 Sep 15;25(18):5638-5649. doi: 10.1158/1078-0432.CCR-19-0924. Epub 2019 Jul 15.
• [9] The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics.J Biol Chem. 2013 Jul 5;288(27):20034-45. doi: 10.1074/jbc.M113.458612. Epub 2013 May 17.
• [10] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [11] Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q.J Biol Chem. 2011 Jul 15;286(28):25211-23. doi: 10.1074/jbc.M111.235028. Epub 2011 Apr 30.
• [12] DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression.Oncogene. 2018 Jan 11;37(2):241-254. doi: 10.1038/onc.2017.323. Epub 2017 Sep 18.
• [13] Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer.J Pathol. 2019 Mar;247(3):381-391. doi: 10.1002/path.5197. Epub 2019 Jan 25.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [21] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [24] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] 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.
• [27] 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.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [29] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [30] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.