Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB2X9TO)

• DOT Name: Probable ATP-dependent RNA helicase DDX46 (DDX46)
• Synonyms: EC 3.6.4.13; DEAD box protein 46; PRP5 homolog
• Gene Name: DDX46
• Related Disease:
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  Amyotrophic lateral sclerosis type 4
  Colorectal carcinoma
  Connective tissue disorder
  Esophageal squamous cell carcinoma
  Hepatitis C virus infection
  Juvenile amyotrophic lateral sclerosis
  Systemic lupus erythematosus
  Werner syndrome
  Small lymphocytic lymphoma
  Systemic sclerosis
  Bone osteosarcoma
  Neoplasm
  Osteosarcoma
• UniProt ID: DDX46_HUMAN
• PDB ID: 6Y50; 6Y53; 6Y5Q; 7EVO; 7Q3L; 7VPX
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MGRESRHYRKRSASRGRSGSRSRSRSPSDKRSKRGDDRRSRSRDRDRRRERSRSRDKRRS
  RSRDRKRLRRSRSRERDRSRERRRSRSRDRRRSRSRSRGRRSRSSSPGNKSKKTENRSRS
  KEKTDGGESSKEKKKDKDDKEDEKEKDAGNFDQNKLEEEMRKRKERVEKWREEQRKKAME
  NIGELKKEIEEMKQGKKWSLEDDDDDEDDPAEAEKEGNEMEGEELDPLDAYMEEVKEEVK
  KFNMRSVKGGGGNEKKSGPTVTKVVTVVTTKKAVVDSDKKKGELMENDQDAMEYSSEEEE
  VDLQTALTGYQTKQRKLLEPVDHGKIEYEPFRKNFYVEVPELAKMSQEEVNVFRLEMEGI
  TVKGKGCPKPIKSWVQCGISMKILNSLKKHGYEKPTPIQTQAIPAIMSGRDLIGIAKTGS
  GKTIAFLLPMFRHIMDQRSLEEGEGPIAVIMTPTRELALQITKECKKFSKTLGLRVVCVY
  GGTGISEQIAELKRGAEIIVCTPGRMIDMLAANSGRVTNLRRVTYVVLDEADRMFDMGFE
  PQVMRIVDNVRPDRQTVMFSATFPRAMEALARRILSKPIEVQVGGRSVVCSDVEQQVIVI
  EEEKKFLKLLELLGHYQESGSVIIFVDKQEHADGLLKDLMRASYPCMSLHGGIDQYDRDS
  IINDFKNGTCKLLVATSVAARGLDVKHLILVVNYSCPNHYEDYVHRAGRTGRAGNKGYAY
  TFITEDQARYAGDIIKALELSGTAVPPDLEKLWSDFKDQQKAEGKIIKKSSGFSGKGFKF
  DETEQALANERKKLQKAALGLQDSDDEDAAVDIDEQIESMFNSKKRVKDMAAPGTSSVPA
  PTAGNAEKLEIAKRLALRINAQKNLGIESQDVMQQATNAILRGGTILAPTVSAKTIAEQL
  AEKINAKLNYVPLEKQEEERQDGGQNESFKRYEEELEINDFPQTARWKVTSKEALQRISE
  YSEAAITIRGTYFPPGKEPKEGERKIYLAIESANELAVQKAKAEITRLIKEELIRLQNSY
  QPTNKGRYKVL
• Function: Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, DDX46 plays essential roles during assembly of pre-spliceosome and proofreading of the branch site.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	DIS84UUI	Definitive	Genetic Variation	[1]
Amyotrophic lateral sclerosis type 4	DISSDHYG	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Connective tissue disorder	DISKXBS3	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[6]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Strong	Genetic Variation	[2]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[4]
Werner syndrome	DISZY45W	Strong	Genetic Variation	[7]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[8]
Systemic sclerosis	DISF44L6	moderate	Biomarker	[7]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[9]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[9]

9 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 Probable ATP-dependent RNA helicase DDX46 (DDX46).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[15]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[19]

4 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 DDX46 (DDX46).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Probable ATP-dependent RNA helicase DDX46 (DDX46).	[17]

References

• [1] Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage.J Clin Neurosci. 2014 Sep;21(9):1627-31. doi: 10.1016/j.jocn.2013.11.048. Epub 2014 May 6.
• [2] DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. doi: 10.1086/421054. Epub 2004 Apr 21.
• [3] Lentiviral DDX46 knockdown inhibits growth and induces apoptosis in human colorectal cancer cells.Gene. 2015 Apr 15;560(2):237-44. doi: 10.1016/j.gene.2015.02.020. Epub 2015 Feb 11.
• [4] Autoantibodies to a nucleolar RNA helicase protein in patients with connective tissue diseases.Arthritis Rheum. 1997 Aug;40(8):1487-92. doi: 10.1002/1529-0131(199708)40:8<1487::AID-ART18>3.0.CO;2-P.
• [5] Knockdown of DDX46 inhibits proliferation and induces apoptosis in esophageal squamous cell carcinoma cells.Oncol Rep. 2016 Jul;36(1):223-30. doi: 10.3892/or.2016.4803. Epub 2016 May 11.
• [6] Induction of cell-mediated immune responses in mice by DNA vaccines that express hepatitis C virus NS3 mutants lacking serine protease and NTPase/RNA helicase activities.PLoS One. 2014 Jun 5;9(6):e98877. doi: 10.1371/journal.pone.0098877. eCollection 2014.
• [7] Werner's syndrome: from clinics to genetics.Clin Exp Rheumatol. 2000 Nov-Dec;18(6):760-6.
• [8] Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment.PLoS One. 2016 Apr 14;11(4):e0148500. doi: 10.1371/journal.pone.0148500. eCollection 2016.
• [9] Knockdown of DDX46 Inhibits the Invasion and Tumorigenesis in Osteosarcoma Cells.Oncol Res. 2017 Mar 13;25(3):417-425. doi: 10.3727/096504016X14747253292210. Epub 2016 Sep 30.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] 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.
• [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] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.