Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUBBA4W)

• DOT Name: Nucleoprotein TPR (TPR)
• Synonyms: Megator; NPC-associated intranuclear protein; Translocated promoter region protein
• Gene Name: TPR
• Related Disease:
  Acute myelogenous leukaemia
  Ependymoma
  Intellectual disability
  Metabolic disorder
  Prostate cancer
  Prostate carcinoma
  Adult glioblastoma
  Advanced cancer
  Bone osteosarcoma
  Cobblestone lissencephaly
  Glioblastoma multiforme
  Hepatitis C virus infection
  Holt-Oram syndrome
  Hutchinson-Gilford progeria syndrome
  Osteosarcoma
  Stomach cancer
  Syphilis
  Thyroid gland papillary carcinoma
  Asthma
  Chronic obstructive pulmonary disease
  Thyroid gland carcinoma
  Thyroid tumor
  Gastric cancer
  Intellectual developmental disorder, autosomal recessive 79
  Neoplasm
  T-lymphoblastic lymphoma
• UniProt ID: TPR_HUMAN
• PDB ID: 5TO5; 5TO6; 5TO7; 5TVB
• Pfam ID: PF07926
• Sequence:
  MAAVLQQVLERTELNKLPKSVQNKLEKFLADQQSEIDGLKGRHEKFKVESEQQYFEIEKR
  LSHSQERLVNETRECQSLRLELEKLNNQLKALTEKNKELEIAQDRNIAIQSQFTRTKEEL
  EAEKRDLIRTNERLSQELEYLTEDVKRLNEKLKESNTTKGELQLKLDELQASDVSVKYRE
  KRLEQEKELLHSQNTWLNTELKTKTDELLALGREKGNEILELKCNLENKKEEVSRLEEQM
  NGLKTSNEHLQKHVEDLLTKLKEAKEQQASMEEKFHNELNAHIKLSNLYKSAADDSEAKS
  NELTRAVEELHKLLKEAGEANKAIQDHLLEVEQSKDQMEKEMLEKIGRLEKELENANDLL
  SATKRKGAILSEEELAAMSPTAAAVAKIVKPGMKLTELYNAYVETQDQLLLEKLENKRIN
  KYLDEIVKEVEAKAPILKRQREEYERAQKAVASLSVKLEQAMKEIQRLQEDTDKANKQSS
  VLERDNRRMEIQVKDLSQQIRVLLMELEEARGNHVIRDEEVSSADISSSSEVISQHLVSY
  RNIEELQQQNQRLLVALRELGETREREEQETTSSKITELQLKLESALTELEQLRKSRQHQ
  MQLVDSIVRQRDMYRILLSQTTGVAIPLHASSLDDVSLASTPKRPSTSQTVSTPAPVPVI
  ESTEAIEAKAALKQLQEIFENYKKEKAENEKIQNEQLEKLQEQVTDLRSQNTKISTQLDF
  ASKRYEMLQDNVEGYRREITSLHERNQKLTATTQKQEQIINTMTQDLRGANEKLAVAEVR
  AENLKKEKEMLKLSEVRLSQQRESLLAEQRGQNLLLTNLQTIQGILERSETETKQRLSSQ
  IEKLEHEISHLKKKLENEVEQRHTLTRNLDVQLLDTKRQLDTETNLHLNTKELLKNAQKE
  IATLKQHLSNMEVQVASQSSQRTGKGQPSNKEDVDDLVSQLRQTEEQVNDLKERLKTSTS
  NVEQYQAMVTSLEESLNKEKQVTEEVRKNIEVRLKESAEFQTQLEKKLMEVEKEKQELQD
  DKRRAIESMEQQLSELKKTLSSVQNEVQEALQRASTALSNEQQARRDCQEQAKIAVEAQN
  KYERELMLHAADVEALQAAKEQVSKMASVRQHLEETTQKAESQLLECKASWEERERMLKD
  EVSKCVCRCEDLEKQNRLLHDQIEKLSDKVVASVKEGVQGPLNVSLSEEGKSQEQILEIL
  RFIRREKEIAETRFEVAQVESLRYRQRVELLERELQELQDSLNAEREKVQVTAKTMAQHE
  ELMKKTETMNVVMETNKMLREEKERLEQDLQQMQAKVRKLELDILPLQEANAELSEKSGM
  LQAEKKLLEEDVKRWKARNQHLVSQQKDPDTEEYRKLLSEKEVHTKRIQQLTEEIGRLKA
  EIARSNASLTNNQNLIQSLKEDLNKVRTEKETIQKDLDAKIIDIQEKVKTITQVKKIGRR
  YKTQYEELKAQQDKVMETSAQSSGDHQEQHVSVQEMQELKETLNQAETKSKSLESQVENL
  QKTLSEKETEARNLQEQTVQLQSELSRLRQDLQDRTTQEEQLRQQITEKEEKTRKAIVAA
  KSKIAHLAGVKDQLTKENEELKQRNGALDQQKDELDVRITALKSQYEGRISRLERELREH
  QERHLEQRDEPQEPSNKVPEQQRQITLKTTPASGERGIASTSDPPTANIKPTPVVSTPSK
  VTAAAMAGNKSTPRASIRPMVTPATVTNPTTTPTATVMPTTQVESQEAMQSEGPVEHVPV
  FGSTSGSVRSTSPNVQPSISQPILTVQQQTQATAFVQPTQQSHPQIEPANQELSSNIVEV
  VQSSPVERPSTSTAVFGTVSATPSSSLPKRTREEEEDSTIEASDQVSDDTVEMPLPKKLK
  SVTPVGTEEEVMAEESTDGEVETQVYNQDSQDSIGEGVTQGDYTPMEDSEETSQSLQIDL
  GPLQSDQQTTTSSQDGQGKGDDVIVIDSDDEEEDDDENDGEHEDYEEDEEDDDDDEDDTG
  MGDEGEDSNEGTGSADGNDGYEADDAEGGDGTDPGTETEESMGGGEGNHRAADSQNSGEG
  NTGAAESSFSQEVSREQQPSSASERQAPRAPQSPRRPPHPLPPRLTIHAPPQELGPPVQR
  IQMTRRQSVGRGLQLTPGIGGMQQHFFDDEDRTVPSTPTLVVPHRTDGFAEAIHSPQVAG
  VPRFRFGPPEDMPQTSSSHSDLGQLASQGGLGMYETPLFLAHEEESGGRSVPTTPLQVAA
  PVTVFTESTTSDASEHASQSVPMVTTSTGTLSTTNETATGDDGDEVFVEAESEGISSEAG
  LEIDSQQEEEPVQASDESDLPSTSQDPPSSSSVDTSSSQPKPFRRVRLQTTLRQGVRGRQ
  FNRQRGVSHAMGGRGGINRGNIN
• Function: Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with NUP153, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Negatively regulates both the association of CTE-containing mRNA with large polyribosomes and translation initiation. Does not play any role in Rev response element (RRE)-mediated export of unspliced mRNAs. Implicated in nuclear export of mRNAs transcribed from heat shock gene promoters; associates both with chromatin in the HSP70 promoter and with mRNAs transcribed from this promoter under stress-induced conditions. Modulates the nucleocytoplasmic transport of activated MAPK1/ERK2 and huntingtin/HTT and may serve as a docking site for the XPO1/CRM1-mediated nuclear export complex. According to some authors, plays a limited role in the regulation of nuclear protein export. Also plays a role as a structural and functional element of the perinuclear chromatin distribution; involved in the formation and/or maintenance of NPC-associated perinuclear heterochromatin exclusion zones (HEZs). Finally, acts as a spatial regulator of the spindle-assembly checkpoint (SAC) response ensuring a timely and effective recruitment of spindle checkpoint proteins like MAD1L1 and MAD2L1 to unattached kinetochore during the metaphase-anaphase transition before chromosome congression. Its N-terminus is involved in activation of oncogenic kinases.
• Tissue Specificity: Expressed in esophagus, ovary, liver, skin, smooth muscles, cerebrum and fetal cerebellum (at protein level). Highest in testis, lung, thymus, spleen and brain, lower levels in heart, liver and kidney.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways in cancer (hsa05200)
  Thyroid cancer (hsa05216)
• Reactome Pathway:
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-168271)
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  Viral Messenger RNA Synthesis (R-HSA-168325)
  NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-168333)
  Regulation of Glucokinase by Glucokinase Regulatory Protein (R-HSA-170822)
  Nuclear import of Rev protein (R-HSA-180746)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  snRNP Assembly (R-HSA-191859)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Nuclear Pore Complex (NPC) Disassembly (R-HSA-3301854)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) (R-HSA-5619107)
  tRNA processing in the nucleus (R-HSA-6784531)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Ependymoma	DISUMRNZ	Definitive	Biomarker	[2]
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[3]
Metabolic disorder	DIS71G5H	Definitive	Genetic Variation	[4]
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[4]
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[7]
Cobblestone lissencephaly	DIS56826	Strong	Genetic Variation	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Holt-Oram syndrome	DISBNDZ2	Strong	Biomarker	[10]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[11]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[7]
Stomach cancer	DISKIJSX	Strong	Biomarker	[12]
Syphilis	DISJ73BS	Strong	Altered Expression	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Genetic Variation	[14]
Asthma	DISW9QNS	moderate	Biomarker	[15]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[15]
Thyroid gland carcinoma	DISMNGZ0	moderate	Biomarker	[16]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[16]
Gastric cancer	DISXGOUK	Limited	Biomarker	[12]
Intellectual developmental disorder, autosomal recessive 79	DISKT87Z	Limited	Autosomal recessive	[17]
Neoplasm	DISZKGEW	Limited	Altered Expression	[18]
T-lymphoblastic lymphoma	DISGFZXW	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Nucleoprotein TPR (TPR).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Nucleoprotein TPR (TPR).	[24]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Nucleoprotein TPR (TPR).	[36]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nucleoprotein TPR (TPR).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Nucleoprotein TPR (TPR).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleoprotein TPR (TPR).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nucleoprotein TPR (TPR).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleoprotein TPR (TPR).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Nucleoprotein TPR (TPR).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nucleoprotein TPR (TPR).	[26]
Marinol	DM70IK5	Approved	Marinol increases the expression of Nucleoprotein TPR (TPR).	[27]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Nucleoprotein TPR (TPR).	[28]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Nucleoprotein TPR (TPR).	[29]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Nucleoprotein TPR (TPR).	[30]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Nucleoprotein TPR (TPR).	[31]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Nucleoprotein TPR (TPR).	[32]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Nucleoprotein TPR (TPR).	[33]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Nucleoprotein TPR (TPR).	[32]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Nucleoprotein TPR (TPR).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Nucleoprotein TPR (TPR).	[34]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nucleoprotein TPR (TPR).	[28]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Nucleoprotein TPR (TPR).	[37]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Nucleoprotein TPR (TPR).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nucleoprotein TPR (TPR).	[39]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Nucleoprotein TPR (TPR).	[40]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of Nucleoprotein TPR (TPR).	[41]
Biotin	DMKMCE1	Investigative	Biotin increases the expression of Nucleoprotein TPR (TPR).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Nucleoprotein TPR (TPR).	[35]

References

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