Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFX1KCG)

• DOT Name: Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1)
• Synonyms: Cytoplasmic dynein intermediate chain 1; Dynein intermediate chain 1, cytosolic; DH IC-1
• Gene Name: DYNC1I1
• Related Disease:
  Glioblastoma multiforme
  Knee osteoarthritis
  Neoplasm
  Osteoarthritis
  Peripheral neuropathy
  Classic lissencephaly
  Gastric cancer
  Stomach cancer
• UniProt ID: DC1I1_HUMAN
• Pfam ID: PF11540 ; PF00400
• Sequence:
  MSDKSDLKAELERKKQRLAQIREEKKRKEEERKKKEADMQQKKEPVQDDSDLDRKRRETE
  ALLQSIGISPEPPLVQPLHFLTWDTCYFHYLVPTPMSPSSKSVSTPSEAGSQDSGDLGPL
  TRTLQWDTDPSVLQLQSDSELGRRLHKLGVSKVTQVDFLPREVVSYSKETQTPLATHQSE
  EDEEDEEMVESKVGQDSELENQDKKQEVKEAPPRELTEEEKQQILHSEEFLIFFDRTIRV
  IERALAEDSDIFFDYSGRELEEKDGDVQAGANLSFNRQFYDEHWSKHRVVTCMDWSLQYP
  ELMVASYNNNEDAPHEPDGVALVWNMKFKKTTPEYVFHCQSSVMSVCFARFHPNLVVGGT
  YSGQIVLWDNRSHRRTPVQRTPLSAAAHTHPVYCVNVVGTQNAHNLITVSTDGKMCSWSL
  DMLSTPQESMELVYNKSKPVAVTGMAFPTGDVNNFVVGSEEGTVYTACRHGSKAGIGEVF
  EGHQGPVTGINCHMAVGPIDFSHLFVTSSFDWTVKLWTTKHNKPLYSFEDNADYVYDVMW
  SPVHPALFACVDGMGRLDLWNLNNDTEVPTASVAIEGASALNRVRWAQAGKEVAVGDSEG
  RIWVYDVGELAVPHNDEWTRFARTLVEIRANRADSEEEGTVELSA
• Function: Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. The intermediate chains mediate the binding of dynein to dynactin via its 150 kDa component (p150-glued) DCTN1. May play a role in mediating the interaction of cytoplasmic dynein with membranous organelles and kinetochores.
• KEGG Pathway:
  Phagosome (hsa04145)
  Motor proteins (hsa04814)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  MHC class II antigen presentation (R-HSA-2132295)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  RHO GTPases Activate Formins (R-HSA-5663220)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Mitotic Prometaphase (R-HSA-68877)
  HCMV Early Events (R-HSA-9609690)
  Aggrephagy (R-HSA-9646399)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[2]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[3]
Classic lissencephaly	DISR8S3S	Limited	Biomarker	[4]
Gastric cancer	DISXGOUK	Limited	Biomarker	[5]
Stomach cancer	DISKIJSX	Limited	Biomarker	[5]

12 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 Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[12]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[13]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cytoplasmic dynein 1 intermediate chain 1 (DYNC1I1).	[15]

References

• [1] Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma.Oncogene. 2019 Feb;38(8):1151-1165. doi: 10.1038/s41388-018-0504-9. Epub 2018 Sep 24.
• [2] Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019 Feb;51(2):230-236.
• [3] Genetic variation associated with bortezomib-induced peripheral neuropathy.Pharmacogenet Genomics. 2011 Mar;21(3):121-9. doi: 10.1097/FPC.0b013e3283436b45.
• [4] Dynein binds and stimulates axonal motility of the endosome adaptor and NEEP21 family member, calcyon.Int J Biochem Cell Biol. 2017 Sep;90:93-102. doi: 10.1016/j.biocel.2017.07.005. Epub 2017 Jul 19.
• [5] TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis.Cancer Med. 2019 Dec;8(17):7299-7312. doi: 10.1002/cam4.2582. Epub 2019 Oct 11.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] 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.
• [9] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] 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.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [15] 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.
• [16] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] 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.