Details of Drug Off-Target (DOT)

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

• DOT Name: Probable ATP-dependent RNA helicase DDX17 (DDX17)
• Synonyms: EC 3.6.4.13; DEAD box protein 17; DEAD box protein p72; DEAD box protein p82; RNA-dependent helicase p72
• Gene Name: DDX17
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Estrogen-receptor positive breast cancer
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
• UniProt ID: DDX17_HUMAN
• PDB ID: 6UV0; 6UV1; 6UV2; 6UV3; 6UV4
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MPTGFVAPILCVLLPSPTREAATVASATGDSASERESAAPAAAPTAEAPPPSVVTRPEPQ
  ALPSPAIRAPLPDLYPFGTMRGGGFGDRDRDRDRGGFGARGGGGLPPKKFGNPGERLRKK
  KWDLSELPKFEKNFYVEHPEVARLTPYEVDELRRKKEITVRGGDVCPKPVFAFHHANFPQ
  YVMDVLMDQHFTEPTPIQCQGFPLALSGRDMVGIAQTGSGKTLAYLLPAIVHINHQPYLE
  RGDGPICLVLAPTRELAQQVQQVADDYGKCSRLKSTCIYGGAPKGPQIRDLERGVEICIA
  TPGRLIDFLESGKTNLRRCTYLVLDEADRMLDMGFEPQIRKIVDQIRPDRQTLMWSATWP
  KEVRQLAEDFLRDYTQINVGNLELSANHNILQIVDVCMESEKDHKLIQLMEEIMAEKENK
  TIIFVETKRRCDDLTRRMRRDGWPAMCIHGDKSQPERDWVLNEFRSGKAPILIATDVASR
  GLDVEDVKFVINYDYPNSSEDYVHRIGRTARSTNKGTAYTFFTPGNLKQARELIKVLEEA
  NQAINPKLMQLVDHRGGGGGGGGRSRYRTTSSANNPNLMYQDECDRRLRGVKDGGRRDSA
  SYRDRSETDRAGYANGSGYGSPNSAFGAQAGQYTYGQGTYGAAAYGTSSYTAQEYGAGTY
  GASSTTSTGRSSQSSSQQFSGIGRSGQQPQPLMSQQFAQPPGATNMIGYMGQTAYQYPPP
  PPPPPPSRK
• Function: As an RNA helicase, unwinds RNA and alters RNA structures through ATP binding and hydrolysis. Involved in multiple cellular processes, including pre-mRNA splicing, alternative splicing, ribosomal RNA processing and miRNA processing, as well as transcription regulation. Regulates the alternative splicing of exons exhibiting specific features. For instance, promotes the inclusion of AC-rich alternative exons in CD44 transcripts. This function requires the RNA helicase activity. Affects NFAT5 and histone macro-H2A.1/MACROH2A1 alternative splicing in a CDK9-dependent manner. In NFAT5, promotes the introduction of alternative exon 4, which contains 2 stop codons and may target NFAT5 exon 4-containing transcripts to nonsense-mediated mRNA decay, leading to the down-regulation of NFAT5 protein. Affects splicing of mediators of steroid hormone signaling pathway, including kinases that phosphorylates ESR1, such as CDK2, MAPK1 and GSK3B, and transcriptional regulators, such as CREBBP, MED1, NCOR1 and NCOR2. By affecting GSK3B splicing, participates in ESR1 and AR stabilization. In myoblasts and epithelial cells, cooperates with HNRNPH1 to control the splicing of specific subsets of exons. In addition to binding mature mRNAs, also interacts with certain pri-microRNAs, including MIR663/miR-663a, MIR99B/miR-99b, and MIR6087/miR-6087. Binds pri-microRNAs on the 3' segment flanking the stem loop via the 5'-[ACG]CAUC[ACU]-3' consensus sequence. Required for the production of subsets of microRNAs, including MIR21 and MIR125B1. May be involved not only in microRNA primary transcript processing, but also stabilization. Participates in MYC down-regulation at high cell density through the production of MYC-targeting microRNAs. Along with DDX5, may be involved in the processing of the 32S intermediate into the mature 28S ribosomal RNA. Promoter-specific transcription regulator, functioning as a coactivator or corepressor depending on the context of the promoter and the transcriptional complex in which it exists. Enhances NFAT5 transcriptional activity. Synergizes with TP53 in the activation of the MDM2 promoter; this activity requires acetylation on lysine residues. May also coactivate MDM2 transcription through a TP53-independent pathway. Coactivates MMP7 transcription. Along with CTNNB1, coactivates MYC, JUN, FOSL1 and cyclin D1/CCND1 transcription. Alone or in combination with DDX5 and/or SRA1 non-coding RNA, plays a critical role in promoting the assembly of proteins required for the formation of the transcription initiation complex and chromatin remodeling leading to coactivation of MYOD1-dependent transcription. This helicase-independent activity is required for skeletal muscle cells to properly differentiate into myotubes. During epithelial-to-mesenchymal transition, coregulates SMAD-dependent transcriptional activity, directly controlling key effectors of differentiation, including miRNAs which in turn directly repress its expression. Plays a role in estrogen and testosterone signaling pathway at several levels. Mediates the use of alternative promoters in estrogen-responsive genes and regulates transcription and splicing of a large number of steroid hormone target genes. Contrary to splicing regulation activity, transcriptional coregulation of the estrogen receptor ESR1 is helicase-independent. Plays a role in innate immunity. Specifically restricts bunyavirus infection, including Rift Valley fever virus (RVFV) or La Crosse virus (LACV), but not vesicular stomatitis virus (VSV), in an interferon- and DROSHA-independent manner. Binds to RVFV RNA, likely via structured viral RNA elements. Promotes mRNA degradation mediated by the antiviral zinc-finger protein ZC3HAV1, in an ATPase-dependent manner.
• Tissue Specificity: Widely expressed . Low expression, if any, in normal colonic epithelial cells (at protein level). Levels tend to increase during colon cancer progression, from very low in benign hyperplastic polyps to very high in tubular and villous adenomas .
• Reactome Pathway: SUMOylation of transcription cofactors (R-HSA-3899300)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Pancreatic cancer	DISJC981	moderate	Biomarker	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Probable ATP-dependent RNA helicase DDX17 (DDX17) decreases the response to substance of Arsenic.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[22]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[23]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[24]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[25]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[26]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[27]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[15]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[15]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[29]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[33]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[36]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[37]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[39]

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 DDX17 (DDX17).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[34]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[34]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Probable ATP-dependent RNA helicase DDX17 (DDX17).	[38]

References

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