Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS0UOL5)

• DOT Name: Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2)
• Synonyms: Cytoplasmic dynein intermediate chain 2; Dynein intermediate chain 2, cytosolic; DH IC-2
• Gene Name: DYNC1I2
• Related Disease:
  Neurodevelopmental disorder with microcephaly and structural brain anomalies
  Intellectual disability
  Isolated congenital microcephaly
• UniProt ID: DC1I2_HUMAN
• PDB ID: 5JPW; 6F1T; 6F1U; 6F1Z; 6F38; 6F3A; 7Z8F; 7Z8I; 7Z8J; 7Z8K
• Pfam ID: PF11540 ; PF00400
• Sequence:
  MSDKSELKAELERKKQRLAQIREEKKRKEEERKKKETDQKKEAVAPVQEESDLEKKRREA
  EALLQSMGLTPESPIVFSEYWVPPPMSPSSKSVSTPSEAGSQDSGDGAVGSRTLHWDTDP
  SVLQLHSDSDLGRGPIKLGMAKITQVDFPPREIVTYTKETQTPVMAQPKEDEEEDDDVVA
  PKPPIEPEEEKTLKKDEENDSKAPPHELTEEEKQQILHSEEFLSFFDHSTRIVERALSEQ
  INIFFDYSGRDLEDKEGEIQAGAKLSLNRQFFDERWSKHRVVSCLDWSSQYPELLVASYN
  NNEDAPHEPDGVALVWNMKYKKTTPEYVFHCQSAVMSATFAKFHPNLVVGGTYSGQIVLW
  DNRSNKRTPVQRTPLSAAAHTHPVYCVNVVGTQNAHNLISISTDGKICSWSLDMLSHPQD
  SMELVHKQSKAVAVTSMSFPVGDVNNFVVGSEEGSVYTACRHGSKAGISEMFEGHQGPIT
  GIHCHAAVGAVDFSHLFVTSSFDWTVKLWTTKNNKPLYSFEDNADYVYDVMWSPTHPALF
  ACVDGMGRLDLWNLNNDTEVPTASISVEGNPALNRVRWTHSGREIAVGDSEGQIVIYDVG
  EQIAVPRNDEWARFGRTLAEINANRADAEEEAATRIPA
• 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. Involved in membrane-transport, such as Golgi apparatus, late endosomes and lysosomes.
• 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)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  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)
  AURKA Activation by TPX2 (R-HSA-8854518)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with microcephaly and structural brain anomalies	DISFZKZ1	Strong	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	moderate	Biomarker	[1]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[1]

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 Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2).	[12]

References

• [1] Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features. Am J Hum Genet. 2019 Jun 6;104(6):1073-1087. doi: 10.1016/j.ajhg.2019.04.002. Epub 2019 May 9.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [9] 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.
• [10] 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.
• [11] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [12] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.