Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBJHS8C)

• DOT Name: Probable ATP-dependent RNA helicase DDX23 (DDX23)
• Synonyms: EC 3.6.4.13; 100 kDa U5 snRNP-specific protein; DEAD box protein 23; PRP28 homolog; U5-100kD
• Gene Name: DDX23
• Related Disease:
  Cardiovascular disease
  Glioma
  Non-small-cell lung cancer
  Aplasia cutis congenita
  Corpus callosum, agenesis of
• UniProt ID: DDX23_HUMAN
• PDB ID: 3JCR; 4NHO; 6AH0; 6QW6; 6QX9
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MAGELADKKDRDASPSKEERKRSRTPDRERDRDRDRKSSPSKDRKRHRSRDRRRGGSRSR
  SRSRSKSAERERRHKERERDKERDRNKKDRDRDKDGHRRDKDRKRSSLSPGRGKDFKSRK
  DRDSKKDEEDEHGDKKPKAQPLSLEELLAKKKAEEEAEAKPKFLSKAEREAEALKRRQQE
  VEERQRMLEEERKKRKQFQDLGRKMLEDPQERERRERRERMERETNGNEDEEGRQKIREE
  KDKSKELHAIKERYLGGIKKRRRTRHLNDRKFVFEWDASEDTSIDYNPLYKERHQVQLLG
  RGFIAGIDLKQQKREQSRFYGDLMEKRRTLEEKEQEEARLRKLRKKEAKQRWDDRHWSQK
  KLDEMTDRDWRIFREDYSITTKGGKIPNPIRSWKDSSLPPHILEVIDKCGYKEPTPIQRQ
  AIPIGLQNRDIIGVAETGSGKTAAFLIPLLVWITTLPKIDRIEESDQGPYAIILAPTREL
  AQQIEEETIKFGKPLGIRTVAVIGGISREDQGFRLRMGCEIVIATPGRLIDVLENRYLVL
  SRCTYVVLDEADRMIDMGFEPDVQKILEHMPVSNQKPDTDEAEDPEKMLANFESGKHKYR
  QTVMFTATMPPAVERLARSYLRRPAVVYIGSAGKPHERVEQKVFLMSESEKRKKLLAILE
  QGFDPPIIIFVNQKKGCDVLAKSLEKMGYNACTLHGGKGQEQREFALSNLKAGAKDILVA
  TDVAGRGIDIQDVSMVVNYDMAKNIEDYIHRIGRTGRAGKSGVAITFLTKEDSAVFYELK
  QAILESPVSSCPPELANHPDAQHKPGTILTKKRREETIFA
• Function: Involved in pre-mRNA splicing and its phosphorylated form (by SRPK2) is required for spliceosomal B complex formation. Independently of its spliceosome formation function, required for the suppression of incorrect R-loops formed during transcription; R-loops are composed of a DNA:RNA hybrid and the associated non-template single-stranded DNA.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Aplasia cutis congenita	DISMDAYM	Limited	Genetic Variation	[4]
Corpus callosum, agenesis of	DISO9P40	Limited	Genetic Variation	[4]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Probable ATP-dependent RNA helicase DDX23 (DDX23) affects the response to substance of Paclitaxel.	[17]
Vinblastine	DM5TVS3	Approved	Probable ATP-dependent RNA helicase DDX23 (DDX23) affects the response to substance of Vinblastine.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[15]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Probable ATP-dependent RNA helicase DDX23 (DDX23).	[13]

References

• [1] 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.
• [2] DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis.Brain. 2015 Sep;138(Pt 9):2553-70. doi: 10.1093/brain/awv167. Epub 2015 Jun 29.
• [3] DDX23-Linc00630-HDAC1 axis activates the Notch pathway to promote metastasis.Oncotarget. 2017 Jun 13;8(24):38937-38949. doi: 10.18632/oncotarget.17156.
• [4] Transcription Dynamics Prevent RNA-Mediated Genomic Instability through SRPK2-Dependent DDX23 Phosphorylation.Cell Rep. 2017 Jan 10;18(2):334-343. doi: 10.1016/j.celrep.2016.12.050.
• [5] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] 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.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [16] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.