Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDO4TRX)

• DOT Name: ATP-dependent RNA helicase DDX3X (DDX3X)
• Synonyms: EC 3.6.4.13; CAP-Rf; DEAD box protein 3, X-chromosomal; DEAD box, X isoform; DBX; Helicase-like protein 2; HLP2
• Gene Name: DDX3X
• Related Disease:
  Intellectual disability, X-linked 102
  Lung neoplasm
  X-linked syndromic intellectual disability
  Adenocarcinoma
  Advanced cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Colitis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epilepsy
  Fatty liver disease
  Hepatitis B virus infection
  Hepatitis C virus infection
  Inflammatory bowel disease
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Malignant mesothelioma
  Matthew-Wood syndrome
  Medulloblastoma
  Metastatic malignant neoplasm
  Neoplasm
  Neurodevelopmental disorder
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Retinoblastoma
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  T-cell lymphoma
  Bone osteosarcoma
  Head-neck squamous cell carcinoma
  Influenza
  Movement disorder
  Osteosarcoma
  T-cell acute lymphoblastic leukaemia
  Toriello-Carey syndrome
  X-linked intellectual disability-hypotonia-movement disorder syndrome
  Amyotrophic lateral sclerosis
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Melanoma
  Osteoarthritis
• UniProt ID: DDX3X_HUMAN
• PDB ID: 2I4I; 2JGN; 3JRV; 4O2C; 4O2E; 4O2F; 4PX9; 4PXA; 5E7I; 5E7J; 5E7M; 6CZ5; 6O5F; 7LIU
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MSHVAVENALGLDQQFAGLDLNSSDNQSGGSTASKGRYIPPHLRNREATKGFYDKDSSGW
  SSSKDKDAYSSFGSRSDSRGKSSFFSDRGSGSRGRFDDRGRSDYDGIGSRGDRSGFGKFE
  RGGNSRWCDKSDEDDWSKPLPPSERLEQELFSGGNTGINFEKYDDIPVEATGNNCPPHIE
  SFSDVEMGEIIMGNIELTRYTRPTPVQKHAIPIIKEKRDLMACAQTGSGKTAAFLLPILS
  QIYSDGPGEALRAMKENGRYGRRKQYPISLVLAPTRELAVQIYEEARKFSYRSRVRPCVV
  YGGADIGQQIRDLERGCHLLVATPGRLVDMMERGKIGLDFCKYLVLDEADRMLDMGFEPQ
  IRRIVEQDTMPPKGVRHTMMFSATFPKEIQMLARDFLDEYIFLAVGRVGSTSENITQKVV
  WVEESDKRSFLLDLLNATGKDSLTLVFVETKKGADSLEDFLYHEGYACTSIHGDRSQRDR
  EEALHQFRSGKSPILVATAVAARGLDISNVKHVINFDLPSDIEEYVHRIGRTGRVGNLGL
  ATSFFNERNINITKDLLDLLVEAKQEVPSWLENMAYEHHYKGSSRGRSKSSRFSGGFGAR
  DYRQSSGASSSSFSSSRASSSRSGGGGHGSSRGFGGGGYGGFYNSDGYGGNYNSQGVDWW
  GN
• Function: Multifunctional ATP-dependent RNA helicase. The ATPase activity can be stimulated by various ribo-and deoxynucleic acids indicative for a relaxed substrate specificity. In vitro can unwind partially double-stranded DNA with a preference for 5'-single-stranded DNA overhangs. Binds RNA G-quadruplex (rG4s) structures, including those located in the 5'-UTR of NRAS mRNA. Involved in many cellular processes, which do not necessarily require its ATPase/helicase catalytic activities (Probable). Involved in transcription regulation. Positively regulates CDKN1A/WAF1/CIP1 transcription in an SP1-dependent manner, hence inhibits cell growth. This function requires its ATPase, but not helicase activity. CDKN1A up-regulation may be cell-type specific. Binds CDH1/E-cadherin promoter and represses its transcription. Potentiates HNF4A-mediated MTTP transcriptional activation; this function requires ATPase, but not helicase activity. Facilitates HNF4A acetylation, possibly catalyzed by CREBBP/EP300, thereby increasing the DNA-binding affinity of HNF4 to its response element. In addition, disrupts the interaction between HNF4 and SHP that forms inactive heterodimers and enhances the formation of active HNF4 homodimers. By promoting HNF4A-induced MTTP expression, may play a role in lipid homeostasis. May positively regulate TP53 transcription. Associates with mRNPs, predominantly with spliced mRNAs carrying an exon junction complex (EJC). Involved in the regulation of translation initiation. Not involved in the general process of translation, but promotes efficient translation of selected complex mRNAs, containing highly structured 5'-untranslated regions (UTR). This function depends on helicase activity. Might facilitate translation by resolving secondary structures of 5'-UTRs during ribosome scanning. Alternatively, may act prior to 43S ribosomal scanning and promote 43S pre-initiation complex entry to mRNAs exhibiting specific RNA motifs, by performing local remodeling of transcript structures located close to the cap moiety. Independently of its ATPase activity, promotes the assembly of functional 80S ribosomes and disassembles from ribosomes prior to the translation elongation process. Positively regulates the translation of cyclin E1/CCNE1 mRNA and consequently promotes G1/S-phase transition during the cell cycle. May activate TP53 translation. Required for endoplasmic reticulum stress-induced ATF4 mRNA translation. Independently of its ATPase/helicase activity, enhances IRES-mediated translation; this activity requires interaction with EIF4E. Independently of its ATPase/helicase activity, has also been shown specifically repress cap-dependent translation, possibly by acting on translation initiation factor EIF4E. Involved in innate immunity, acting as a viral RNA sensor. Binds viral RNAs and promotes the production of type I interferon (IFN-alpha and IFN-beta). Potentiate MAVS/RIGI-mediated induction of IFNB in early stages of infection. Enhances IFNB1 expression via IRF3/IRF7 pathway and participates in NFKB activation in the presence of MAVS and TBK1. Involved in TBK1 and IKBKE-dependent IRF3 activation leading to IFNB induction, acts as a scaffolding adapter that links IKBKE and IRF3 and coordinates their activation. Involved in the TLR7/TLR8 signaling pathway leading to type I interferon induction, including IFNA4 production. In this context, acts as an upstream regulator of IRF7 activation by MAP3K14/NIK and CHUK/IKKA. Stimulates CHUK autophosphorylation and activation following physiological activation of the TLR7 and TLR8 pathways, leading to MAP3K14/CHUK-mediated activatory phosphorylation of IRF7. Also stimulates MAP3K14/CHUK-dependent NF-kappa-B signaling. Negatively regulates TNF-induced IL6 and IL8 expression, via the NF-kappa-B pathway. May act by interacting with RELA/p65 and trapping it in the cytoplasm. May also bind IFNB promoter; the function is independent of IRF3. Involved in both stress and inflammatory responses. Independently of its ATPase/helicase activity, required for efficient stress granule assembly through its interaction with EIF4E, hence promotes survival in stressed cells. Independently of its helicase activity, regulates NLRP3 inflammasome assembly through interaction with NLRP3 and hence promotes cell death by pyroptosis during inflammation. This function is independent of helicase activity. Therefore DDX3X availability may be used to interpret stress signals and choose between pro-survival stress granules and pyroptotic NLRP3 inflammasomes and serve as a live-or-die checkpoint in stressed cells. In association with GSK3A/B, negatively regulates extrinsic apoptotic signaling pathway via death domain receptors, including TNFRSF10B, slowing down the rate of CASP3 activation following death receptor stimulation. Cleavage by caspases may inactivate DDX3X and relieve the inhibition. Independently of its ATPase/helicase activity, allosteric activator of CSNK1E. Stimulates CSNK1E-mediated phosphorylation of DVL2, thereby involved in the positive regulation of Wnt/beta-catenin signaling pathway. Also activates CSNK1A1 and CSNK1D in vitro, but it is uncertain if these targets are physiologically relevant. ATPase and casein kinase-activating functions are mutually exclusive. May be involved in mitotic chromosome segregation ; (Microbial infection) Facilitates hepatitis C virus (HCV) replication. During infection, HCV core protein inhibits the interaction between MAVS and DDX3X and therefore impairs MAVS-dependent INFB induction and might recruit DDX3X to HCV replication complex ; (Microbial infection) Facilitates HIV-1 replication. Acts as a cofactor for XPO1-mediated nuclear export of HIV-1 Rev RNAs. This function is strongly stimulated in the presence of TBK1 and requires DDX3X ATPase activity ; (Microbial infection) Facilitates Zika virus (ZIKV) replication; (Microbial infection) Facilitates Dengue virus (DENV) replication; (Microbial infection) Facilitates Venezuelan equine encephalitis virus (VEEV) replication.
• Tissue Specificity: Widely expressed . In testis, expressed in spermatids . Expressed in epidermis and liver (at protein level) .
• KEGG Pathway:
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Hepatitis B (hsa05161)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked 102	DISLT56E	Definitive	X-linked	[1]
Lung neoplasm	DISVARNB	Definitive	Biomarker	[2]
X-linked syndromic intellectual disability	DISG1YOH	Definitive	X-linked	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Colitis	DISAF7DD	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[11]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[11]
Epilepsy	DISBB28L	Strong	Biomarker	[12]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[13]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[14]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[13]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[15]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[16]
Lung cancer	DISCM4YA	Strong	Altered Expression	[17]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[18]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[19]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[4]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[20]
Neoplasm	DISZKGEW	Strong	Altered Expression	[21]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[22]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[18]
Prostate cancer	DISF190Y	Strong	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[25]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[26]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[27]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[28]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[29]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[30]
Influenza	DIS3PNU3	moderate	Biomarker	[31]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[16]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[29]
T-cell acute lymphoblastic leukaemia	DIS17AI2	moderate	FusionGene	[32]
Toriello-Carey syndrome	DISZTO2J	Supportive	Autosomal recessive	[33]
X-linked intellectual disability-hypotonia-movement disorder syndrome	DIS06AMV	Supportive	X-linked	[34]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[35]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[36]
Liver cancer	DISDE4BI	Limited	Altered Expression	[36]
Melanoma	DIS1RRCY	Limited	Altered Expression	[37]
Osteoarthritis	DIS05URM	Limited	Biomarker	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ATP-dependent RNA helicase DDX3X (DDX3X).	[39]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ATP-dependent RNA helicase DDX3X (DDX3X).	[52]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[40]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[41]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[42]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[43]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[44]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[46]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[47]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[48]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[49]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[50]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[51]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[53]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[54]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[55]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[56]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of ATP-dependent RNA helicase DDX3X (DDX3X).	[57]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the degradation of ATP-dependent RNA helicase DDX3X (DDX3X).	[45]
D-glucose	DMMG2TO	Investigative	D-glucose increases the degradation of ATP-dependent RNA helicase DDX3X (DDX3X).	[45]

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