Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6KEIHP)

• DOT Name: Probable ATP-dependent RNA helicase DDX41 (DDX41)
• Synonyms: EC 3.6.4.13; DEAD box protein 41; DEAD box protein abstrakt homolog
• Gene Name: DDX41
• Related Disease:
  DDX41-related hematologic malignancy predisposition syndrome
  Hepatitis C virus infection
  Leukemia
  Li-Fraumeni syndrome
  Melanoma
  Sarcoidosis
  Severe congenital neutropenia
  Sexually transmitted infection
  Influenza
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Advanced cancer
  Childhood myelodysplastic syndrome
  Chronic myelomonocytic leukemia
  leukaemia
  Myelodysplastic syndrome
  Myeloid neoplasm
  Myeloproliferative neoplasm
  Neoplasm
  Syphilis
• UniProt ID: DDX41_HUMAN
• PDB ID: 2P6N; 5GVR; 5GVS; 5H1Y; 8C6J
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MEESEPERKRARTDEVPAGGSRSEAEDEDDEDYVPYVPLRQRRQLLLQKLLQRRRKGAAE
  EEQQDSGSEPRGDEDDIPLGPQSNVSLLDQHQHLKEKAEARKESAKEKQLKEEEKILESV
  AEGRALMSVKEMAKGITYDDPIKTSWTPPRYVLSMSEERHERVRKKYHILVEGDGIPPPI
  KSFKEMKFPAAILRGLKKKGIHHPTPIQIQGIPTILSGRDMIGIAFTGSGKTLVFTLPVI
  MFCLEQEKRLPFSKREGPYGLIICPSRELARQTHGILEYYCRLLQEDSSPLLRCALCIGG
  MSVKEQMETIRHGVHMMVATPGRLMDLLQKKMVSLDICRYLALDEADRMIDMGFEGDIRT
  IFSYFKGQRQTLLFSATMPKKIQNFAKSALVKPVTINVGRAGAASLDVIQEVEYVKEEAK
  MVYLLECLQKTPPPVLIFAEKKADVDAIHEYLLLKGVEAVAIHGGKDQEERTKAIEAFRE
  GKKDVLVATDVASKGLDFPAIQHVINYDMPEEIENYVHRIGRTGRSGNTGIATTFINKAC
  DESVLMDLKALLLEAKQKVPPVLQVLHCGDESMLDIGGERGCAFCGGLGHRITDCPKLEA
  MQTKQVSNIGRKDYLAHSSMDF
• Function: Probable ATP-dependent RNA helicase. Is required during post-transcriptional gene expression. May be involved in pre-mRNA splicing.
• KEGG Pathway: Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975)
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  STING mediated induction of host immune responses (R-HSA-1834941)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
DDX41-related hematologic malignancy predisposition syndrome	DISU6FRL	Definitive	Autosomal dominant	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[2]
Leukemia	DISNAKFL	Strong	Genetic Variation	[3]
Li-Fraumeni syndrome	DISR64XA	Strong	Genetic Variation	[4]
Melanoma	DIS1RRCY	Strong	Altered Expression	[5]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[6]
Severe congenital neutropenia	DISES99N	Strong	Biomarker	[7]
Sexually transmitted infection	DISIVIAL	Strong	Biomarker	[8]
Influenza	DIS3PNU3	moderate	Biomarker	[9]
Acute lymphocytic leukaemia	DISPX75S	Limited	Altered Expression	[10]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[11]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[3]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Genetic Variation	[12]
Chronic myelomonocytic leukemia	DISIL8UR	Limited	Genetic Variation	[11]
leukaemia	DISS7D1V	Limited	Genetic Variation	[3]
Myelodysplastic syndrome	DISYHNUI	Limited	Genetic Variation	[11]
Myeloid neoplasm	DIS2YOWO	Limited	Genetic Variation	[13]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[11]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[3]
Syphilis	DISJ73BS	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Probable ATP-dependent RNA helicase DDX41 (DDX41).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Probable ATP-dependent RNA helicase DDX41 (DDX41).	[16]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Probable ATP-dependent RNA helicase DDX41 (DDX41).	[17]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Probable ATP-dependent RNA helicase DDX41 (DDX41).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Probable ATP-dependent RNA helicase DDX41 (DDX41).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Probable ATP-dependent RNA helicase DDX41 (DDX41).	[20]

2 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 Probable ATP-dependent RNA helicase DDX41 (DDX41).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Probable ATP-dependent RNA helicase DDX41 (DDX41).	[21]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Endoscopic Therapy is Effective for Recurrent Anastomotic Biliary Strictures after Orthotopic Liver Transplantation.Ann Hepatol. 2017 November-December,;16(6):924-931. doi: 10.5604/01.3001.0010.5284.
• [3] Novel DDX41 variants in Thai patients with myeloid neoplasms.Int J Hematol. 2020 Feb;111(2):241-246. doi: 10.1007/s12185-019-02770-3. Epub 2019 Nov 11.
• [4] Hereditary myeloid malignancies.Best Pract Res Clin Haematol. 2019 Jun;32(2):163-176. doi: 10.1016/j.beha.2019.05.001. Epub 2019 May 3.
• [5] mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties.Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):637-42. doi: 10.1073/pnas.022637199.
• [6] Putative new childhood leukemia cancer predisposition syndrome caused by germline bi-allelic missense mutations in DDX41.Genes Chromosomes Cancer. 2018 Dec;57(12):670-674. doi: 10.1002/gcc.22680. Epub 2018 Oct 11.
• [7] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [8] Poor correlation between reactive syphilis serology and human immunodeficiency virus testing among potential cornea donors.Am J Ophthalmol. 1995 Jan;119(1):1-6. doi: 10.1016/s0002-9394(14)73806-1.
• [9] Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses.Nat Commun. 2019 Oct 11;10(1):4624. doi: 10.1038/s41467-019-12632-5.
• [10] Expression of DHX32 in lymphoid tissues.Exp Mol Pathol. 2005 Dec;79(3):219-23. doi: 10.1016/j.yexmp.2005.07.002. Epub 2005 Sep 21.
• [11] DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease.Am J Hematol. 2019 Jul;94(7):757-766. doi: 10.1002/ajh.25486. Epub 2019 May 7.
• [12] High-Throughput Screening to Identify Inhibitors of DEAD Box Helicase DDX41.SLAS Discov. 2017 Oct;22(9):1084-1092. doi: 10.1177/2472555217705952. Epub 2017 Apr 20.
• [13] Myeloid neoplasms with germline DDX41 mutation.Int J Hematol. 2017 Aug;106(2):163-174. doi: 10.1007/s12185-017-2260-y. Epub 2017 May 25.
• [14] Prevalence of Treponema pallidum DNA among blood donors with two different serologic tests profiles for syphilis in So Paulo, Brazil.Vox Sang. 2014 May;106(4):376-8. doi: 10.1111/vox.12111.
• [15] 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.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-alpha, CH11 and CYC202. Endocr Relat Cancer. 2007 Jun;14(2):305-15. doi: 10.1677/ERC-06-0003.
• [18] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] 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.
• [21] 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.