Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT63I0CL)

• DOT Name: Dedicator of cytokinesis protein 5 (DOCK5)
• Gene Name: DOCK5
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Asthma
  Obesity
  Osteoporosis
  Head-neck squamous cell carcinoma
  Neoplasm
• UniProt ID: DOCK5_HUMAN
• PDB ID: 7DPA
• Pfam ID: PF06920 ; PF20422 ; PF20421 ; PF14429 ; PF16172 ; PF00018
• Sequence:
  MARWIPTKRQKYGVAIYNYNASQDVELSLQIGDTVHILEMYEGWYRGYTLQNKSKKGIFP
  ETYIHLKEATVEDLGQHETVIPGELPLVQELTSTLREWAVIWRKLYVNNKLTLFRQLQQM
  TYSLIEWRSQILSGTLPKDELAELKKKVTAKIDHGNRMLGLDLVVRDDNGNILDPDETST
  IALFKAHEVASKRIEEKIQEEKSILQNLDLRGQSIFSTIHTYGLYVNFKNFVCNIGEDAE
  LFMALYDPDQSTFISENYLIRWGSNGMPKEIEKLNNLQAVFTDLSSMDLIRPRVSLVCQI
  VRVGHMELKEGKKHTCGLRRPFGVAVMDITDIIHGKVDDEEKQHFIPFQQIAMETYIRQR
  QLIMSPLITSHVIGENEPLTSVLNKVIAAKEVNHKGQGLWVSLKLLPGDLTQVQKNFSHL
  VDRSTAIARKMGFPEIILPGDVRNDIYVTLIHGEFDKGKKKTPKNVEVTMSVHDEEGKLL
  EKAIHPGAGYEGISEYKSVVYYQVKQPCWYETVKVSIAIEEVTRCHIRFTFRHRSSQETR
  DKSERAFGVAFVKLMNPDGTTLQDGRHDLVVYKGDNKKMEDAKFYLTLPGTKMEMEEKEL
  QASKNLVTFTPSKDSTKDSFQIATLICSTKLTQNVDLLGLLNWRSNSQNIKHNLKKLMEV
  DGGEIVKFLQDTLDALFNIMMEMSDSETYDFLVFDALVFIISLIGDIKFQHFNPVLETYI
  YKHFSATLAYVKLSKVLNFYVANADDSSKTELLFAALKALKYLFRFIIQSRVLYLRFYGQ
  SKDGDEFNNSIRQLFLAFNMLMDRPLEEAVKIKGAALKYLPSIINDVKLVFDPVELSVLF
  CKFIQSIPDNQLVRQKLNCMTKIVESTLFRQSECREVLLPLLTDQLSGQLDDNSNKPDHE
  ASSQLLSNILEVLDRKDVGATAVHIQLIMERLLRRINRTVIGMNRQSPHIGSFVACMIAL
  LQQMDDSHYSHYISTFKTRQDIIDFLMETFIMFKDLIGKNVYAKDWMVMNMTQNRVFLRA
  INQFAEVLTRFFMDQASFELQLWNNYFHLAVAFLTHESLQLETFSQAKRNKIVKKYGDMR
  KEIGFRIRDMWYNLGPHKIKFIPSMVGPILEVTLTPEVELRKATIPIFFDMMQCEFNFSG
  NGNFHMFENELITKLDQEVEGGRGDEQYKVLLEKLLLEHCRKHKYLSSSGEVFALLVSSL
  LENLLDYRTIIMQDESKENRMSCTVNVLNFYKEKKREDIYIRYLYKLRDLHRDCENYTEA
  AYTLLLHAELLQWSDKPCVPHLLQKDSYYVYTQQELKEKLYQEIISYFDKGKMWEKAIKL
  SKELAETYESKVFDYEGLGNLLKKRASFYENIIKAMRPQPEYFAVGYYGQGFPSFLRNKI
  FIYRGKEYERREDFSLRLLTQFPNAEKMTSTTPPGEDIKSSPKQYMQCFTVKPVMSLPPS
  YKDKPVPEQILNYYRANEVQQFRYSRPFRKGEKDPDNEFATMWIERTTYTTAYTFPGILK
  WFEVKQISTEEISPLENAIETMELTNERISNCVQQHAWDRSLSVHPLSMLLSGIVDPAVM
  GGFSNYEKAFFTEKYLQEHPEDQEKVELLKRLIALQMPLLTEGIRIHGEKLTEQLKPLHE
  RLSSCFRELKEKVEKHYGVITLPPNLTERKQSRTGSIVLPYIMSSTLRRLSITSVTSSVV
  STSSNSSDNAPSRPGSDGSILEPLLERRASSGARVEDLSLREENSENRISKFKRKDWSLS
  KSQVIAEKAPEPDLMSPTRKAQRPKSLQLMDNRLSPFHGSSPPQSTPLSPPPLTPKATRT
  LSSPSLQTDGIAATPVPPPPPPKSKPYEGSQRNSTELAPPLPVRREAKAPPPPPPKARKS
  GIPTSEPGSQ
• Function: Guanine nucleotide exchange factor (GEF) for Rho and Rac. GEF proteins activate small GTPases by exchanging bound GDP for free GTP. Along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on type IV collagen.
• Reactome Pathway:
  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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Asthma	DISW9QNS	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[3]
Osteoporosis	DISF2JE0	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[5]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[5]

16 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 5 (DOCK5).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dedicator of cytokinesis protein 5 (DOCK5).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dedicator of cytokinesis protein 5 (DOCK5).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Dedicator of cytokinesis protein 5 (DOCK5).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Dedicator of cytokinesis protein 5 (DOCK5).	[22]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Dedicator of cytokinesis protein 5 (DOCK5).	[18]

References

• [1] MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia.FASEB J. 2019 Apr;33(4):5268-5286. doi: 10.1096/fj.201801035R. Epub 2019 Jan 22.
• [2] CDC42-related genes are upregulated in helper Tcells from obese asthmatic children.J Allergy Clin Immunol. 2018 Feb;141(2):539-548.e7. doi: 10.1016/j.jaci.2017.04.016. Epub 2017 May 4.
• [3] Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity.Hum Mol Genet. 2012 Aug 15;21(16):3727-38. doi: 10.1093/hmg/dds187. Epub 2012 May 16.
• [4] Allosteric inhibition of the guanine nucleotide exchange factor DOCK5 by a small molecule.Sci Rep. 2017 Oct 31;7(1):14409. doi: 10.1038/s41598-017-13619-2.
• [5] Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant.Clin Cancer Res. 2018 Oct 15;24(20):5123-5132. doi: 10.1158/1078-0432.CCR-18-0752. Epub 2018 Jun 26.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] 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.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [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] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [18] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [19] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [22] 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.
• [23] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.