Details of Drug Off-Target (DOT)

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

• DOT Name: Dedicator of cytokinesis protein 7 (DOCK7)
• Gene Name: DOCK7
• Related Disease:
  Infantile spasm
  Adult glioblastoma
  Cardiovascular disease
  Coronary atherosclerosis
  Coronary heart disease
  Developmental and epileptic encephalopathy, 23
  Glioblastoma multiforme
  Gray platelet syndrome
  Hyperlipidemia
  Hypochondroplasia
  Platelet storage pool deficiency
  Crohn disease
• UniProt ID: DOCK7_HUMAN
• PDB ID: 6AJ4; 6AJL
• Pfam ID: PF06920 ; PF20422 ; PF20421 ; PF14429 ; PF11878
• Sequence:
  MAERRAFAQKISRTVAAEVRKQISGQYSGSPQLLKNLNIVGNISHHTTVPLTEAVDPVDL
  EDYLITHPLAVDSGPLRDLIEFPPDDIEVVYSPRDCRTLVSAVPEESEMDPHVRDCIRSY
  TEDWAIVIRKYHKLGTGFNPNTLDKQKERQKGLPKQVFESDEAPDGNSYQDDQDDLKRRS
  MSIDDTPRGSWACSIFDLKNSLPDALLPNLLDRTPNEEIDRQNDDQRKSNRHKELFALHP
  SPDEEEPIERLSVPDIPKEHFGQRLLVKCLSLKFEIEIEPIFASLALYDVKEKKKISENF
  YFDLNSEQMKGLLRPHVPPAAITTLARSAIFSITYPSQDVFLVIKLEKVLQQGDIGECAE
  PYMIFKEADATKNKEKLEKLKSQADQFCQRLGKYRMPFAWTAIHLMNIVSSAGSLERDST
  EVEISTGERKGSWSERRNSSIVGRRSLERTTSGDDACNLTSFRPATLTVTNFFKQEGDRL
  SDEDLYKFLADMRRPSSVLRRLRPITAQLKIDISPAPENPHYCLTPELLQVKLYPDSRVR
  PTREILEFPARDVYVPNTTYRNLLYIYPQSLNFANRQGSARNITVKVQFMYGEDPSNAMP
  VIFGKSSCSEFSKEAYTAVVYHNRSPDFHEEIKVKLPATLTDHHHLLFTFYHVSCQQKQN
  TPLETPVGYTWIPMLQNGRLKTGQFCLPVSLEKPPQAYSVLSPEVPLPGMKWVDNHKGVF
  NVEVVAVSSIHTQDPYLDKFFALVNALDEHLFPVRIGDMRIMENNLENELKSSISALNSS
  QLEPVVRFLHLLLDKLILLVIRPPVIAGQIVNLGQASFEAMASIINRLHKNLEGNHDQHG
  RNSLLASYIHYVFRLPNTYPNSSSPGPGGLGGSVHYATMARSAVRPASLNLNRSRSLSNS
  NPDISGTPTSPDDEVRSIIGSKGLDRSNSWVNTGGPKAAPWGSNPSPSAESTQAMDRSCN
  RMSSHTETSSFLQTLTGRLPTKKLFHEELALQWVVCSGSVRESALQQAWFFFELMVKSMV
  HHLYFNDKLEAPRKSRFPERFMDDIAALVSTIASDIVSRFQKDTEMVERLNTSLAFFLND
  LLSVMDRGFVFSLIKSCYKQVSSKLYSLPNPSVLVSLRLDFLRIICSHEHYVTLNLPCSL
  LTPPASPSPSVSSATSQSSGFSTNVQDQKIANMFELSVPFRQQHYLAGLVLTELAVILDP
  DAEGLFGLHKKVINMVHNLLSSHDSDPRYSDPQIKARVAMLYLPLIGIIMETVPQLYDFT
  ETHNQRGRPICIATDDYESESGSMISQTVAMAIAGTSVPQLTRPGSFLLTSTSGRQHTTF
  SAESSRSLLICLLWVLKNADETVLQKWFTDLSVLQLNRLLDLLYLCVSCFEYKGKKVFER
  MNSLTFKKSKDMRAKLEEAILGSIGARQEMVRRSRGQLGTYTIASPPERSPSGSAFGSQE
  NLRWRKDMTHWRQNTEKLDKSRAEIEHEALIDGNLATEANLIILDTLEIVVQTVSVTESK
  ESILGGVLKVLLHSMACNQSAVYLQHCFATQRALVSKFPELLFEEETEQCADLCLRLLRH
  CSSSIGTIRSHASASLYLLMRQNFEIGNNFARVKMQVTMSLSSLVGTSQNFNEEFLRRSL
  KTILTYAEEDLELRETTFPDQVQDLVFNLHMILSDTVKMKEHQEDPEMLIDLMYRIAKGY
  QTSPDLRLTWLQNMAGKHSERSNHAEAAQCLVHSAALVAEYLSMLEDRKYLPVGCVTFQN
  ISSNVLEESAVSDDVVSPDEEGICSGKYFTESGLVGLLEQAAASFSMAGMYEAVNEVYKV
  LIPIHEANRDAKKLSTIHGKLQEAFSKIVHQSTGWERMFGTYFRVGFYGTKFGDLDEQEF
  VYKEPAITKLAEISHRLEGFYGERFGEDVVEVIKDSNPVDKCKLDPNKAYIQITYVEPYF
  DTYEMKDRITYFDKNYNLRRFMYCTPFTLDGRAHGELHEQFKRKTILTTSHAFPYIKTRV
  NVTHKEEIILTPIEVAIEDMQKKTQELAFATHQDPADPKMLQMVLQGSVGTTVNQGPLEV
  AQVFLSEIPSDPKLFRHHNKLRLCFKDFTKRCEDALRKNKSLIGPDQKEYQRELERNYHR
  LKEALQPLINRKIPQLYKAVLPVTCHRDSFSRMSLRKMDL
• Function: Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP. Does not have a GEF activity for CDC42. Required for STMN1 'Ser-15' phosphorylation during axon formation and consequently for neuronal polarization. As part of the DISP complex, may regulate the association of septins with actin and thereby regulate the actin cytoskeleton. Has a role in pigmentation. Involved in the regulation of cortical neurogenesis through the control of radial glial cells (RGCs) proliferation versus differentiation; negatively regulates the basal-to-apical interkinetic nuclear migration of RGCs by antagonizing the microtubule growth-promoting function of TACC3.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  MET activates RAP1 and RAC1 (R-HSA-8875555)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal recessive	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[4]
Developmental and epileptic encephalopathy, 23	DIS0CS3T	Strong	Autosomal recessive	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Gray platelet syndrome	DISLOTCW	Strong	Biomarker	[6]
Hyperlipidemia	DIS61J3S	Strong	Genetic Variation	[7]
Hypochondroplasia	DISHNE51	Strong	Genetic Variation	[7]
Platelet storage pool deficiency	DISHODOH	Strong	Biomarker	[8]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[9]

4 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 Dedicator of cytokinesis protein 7 (DOCK7).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Dedicator of cytokinesis protein 7 (DOCK7).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dedicator of cytokinesis protein 7 (DOCK7).	[19]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the phosphorylation of Dedicator of cytokinesis protein 7 (DOCK7).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[12]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[17]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Dedicator of cytokinesis protein 7 (DOCK7).	[20]

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] Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation.Br J Cancer. 2014 Mar 4;110(5):1307-15. doi: 10.1038/bjc.2014.39. Epub 2014 Feb 11.
• [3] 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.
• [4] DOCK7-ANGPTL3 SNPs and their haplotypes with serum lipid levels and the risk of coronary artery disease and ischemic stroke.Lipids Health Dis. 2018 Feb 17;17(1):30. doi: 10.1186/s12944-018-0677-9.
• [5] Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness. Am J Hum Genet. 2014 Jun 5;94(6):891-7. doi: 10.1016/j.ajhg.2014.04.012. Epub 2014 May 8.
• [6] Nbeal2 interacts with Dock7, Sec16a, and Vac14.Blood. 2018 Mar 1;131(9):1000-1011. doi: 10.1182/blood-2017-08-800359. Epub 2017 Nov 29.
• [7] Association of the variants and haplotypes in the DOCK7, PCSK9 and GALNT2 genes and the risk of hyperlipidaemia.J Cell Mol Med. 2016 Feb;20(2):243-65. doi: 10.1111/jcmm.12713. Epub 2015 Oct 23.
• [8] Misty (m) affects growth traits.Am J Physiol. 1998 Jul;275(1):R29-32. doi: 10.1152/ajpregu.1998.275.1.R29.
• [9] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] 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.
• [13] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [14] 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.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] 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.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] 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.
• [19] 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.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [21] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.