Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3U0ABN)

• DOT Name: Pre-mRNA-processing factor 6 (PRPF6)
• Synonyms: Androgen receptor N-terminal domain-transactivating protein 1; ANT-1; PRP6 homolog; U5 snRNP-associated 102 kDa protein; U5-102 kDa protein
• Gene Name: PRPF6
• Related Disease:
  Cardiomyopathy
  Advanced cancer
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Bullous pemphigoid
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Kearns-Sayre syndrome
  MELAS syndrome
  Metabolic disorder
  Multiple sclerosis
  Myopathy
  Neoplasm
  Pemphigus
  Retinitis pigmentosa 60
  Type-1/2 diabetes
  Colon cancer
  Colon carcinoma
  Retinitis pigmentosa
  Bipolar disorder
  Lymphoma
  Mitochondrial disease
  Mitochondrial myopathy
  Progressive external ophthalmoplegia
  Rett syndrome
• UniProt ID: PRP6_HUMAN
• PDB ID: 3JCR; 5O9Z; 6AH0; 6AHD; 6QW6; 6QX9
• Pfam ID: PF06424 ; PF13432 ; PF14559
• Sequence:
  MNKKKKPFLGMPAPLGYVPGLGRGATGFTTRSDIGPARDANDPVDDRHAPPGKRTVGDQM
  KKNQAADDDDEDLNDTNYDEFNGYAGSLFSSGPYEKDDEEADAIYAALDKRMDERRKERR
  EQREKEEIEKYRMERPKIQQQFSDLKRKLAEVTEEEWLSIPEVGDARNKRQRNPRYEKLT
  PVPDSFFAKHLQTGENHTSVDPRQTQFGGLNTPYPGGLNTPYPGGMTPGLMTPGTGELDM
  RKIGQARNTLMDMRLSQVSDSVSGQTVVDPKGYLTDLNSMIPTHGGDINDIKKARLLLKS
  VRETNPHHPPAWIASARLEEVTGKLQVARNLIMKGTEMCPKSEDVWLEAARLQPGDTAKA
  VVAQAVRHLPQSVRIYIRAAELETDIRAKKRVLRKALEHVPNSVRLWKAAVELEEPEDAR
  IMLSRAVECCPTSVELWLALARLETYENARKVLNKARENIPTDRHIWITAAKLEEANGNT
  QMVEKIIDRAITSLRANGVEINREQWIQDAEECDRAGSVATCQAVMRAVIGIGIEEEDRK
  HTWMEDADSCVAHNALECARAIYAYALQVFPSKKSVWLRAAYFEKNHGTRESLEALLQRA
  VAHCPKAEVLWLMGAKSKWLAGDVPAARSILALAFQANPNSEEIWLAAVKLESENDEYER
  ARRLLAKARSSAPTARVFMKSVKLEWVQDNIRAAQDLCEEALRHYEDFPKLWMMKGQIEE
  QKEMMEKAREAYNQGLKKCPHSTPLWLLLSRLEEKIGQLTRARAILEKSRLKNPKNPGLW
  LESVRLEYRAGLKNIANTLMAKALQECPNSGILWSEAIFLEARPQRRTKSVDALKKCEHD
  PHVLLAVAKLFWSQRKITKAREWFHRTVKIDSDLGDAWAFFYKFELQHGTEEQQEEVRKR
  CESAEPRHGELWCAVSKDIANWQKKIGDILRLVAGRIKNTF
• Function: Involved in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex, one of the building blocks of the spliceosome. Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but does not affect estrogen-induced transactivation.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Bullous pemphigoid	DISOJLKV	Strong	Biomarker	[5]
Dilated cardiomyopathy	DISX608J	Strong	Altered Expression	[6]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[6]
Kearns-Sayre syndrome	DIS9UK5R	Strong	Altered Expression	[7]
MELAS syndrome	DIS81Z3S	Strong	Altered Expression	[7]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[8]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[9]
Myopathy	DISOWG27	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Pemphigus	DISZAZ6M	Strong	Biomarker	[5]
Retinitis pigmentosa 60	DISP0K5Y	Strong	Autosomal dominant	[12]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[8]
Colon cancer	DISVC52G	moderate	Biomarker	[2]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[2]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[13]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[14]
Lymphoma	DISN6V4S	Limited	Biomarker	[15]
Mitochondrial disease	DISKAHA3	Limited	Genetic Variation	[16]
Mitochondrial myopathy	DIS9SA7V	Limited	Genetic Variation	[17]
Progressive external ophthalmoplegia	DISX4ATI	Limited	Genetic Variation	[14]
Rett syndrome	DISGG5UV	Limited	Biomarker	[18]

4 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 Pre-mRNA-processing factor 6 (PRPF6).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Pre-mRNA-processing factor 6 (PRPF6).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Pre-mRNA-processing factor 6 (PRPF6).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Pre-mRNA-processing factor 6 (PRPF6).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[23]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[24]
Selenium	DM25CGV	Approved	Selenium increases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[25]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[26]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[25]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[31]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Pre-mRNA-processing factor 6 (PRPF6).	[32]

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 Pre-mRNA-processing factor 6 (PRPF6).	[28]

References

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• [8] Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity.Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2705-2710. doi: 10.1073/pnas.1700997114. Epub 2017 Feb 21.
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• [11] Over-expression of adenine nucleotide translocase 1 (ANT1) induces apoptosis and tumor regression in vivo.BMC Cancer. 2008 Jun 4;8:160. doi: 10.1186/1471-2407-8-160.
• [12] A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa. Am J Hum Genet. 2011 May 13;88(5):643-9. doi: 10.1016/j.ajhg.2011.04.008. Epub 2011 May 5.
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• [16] The inner mitochondrial membrane protein ANT1 modulates IL-6 expression via the JNK pathway in macrophages.FEBS Lett. 2018 Nov;592(22):3750-3758. doi: 10.1002/1873-3468.13269. Epub 2018 Oct 24.
• [17] Dominant membrane uncoupling by mutant adenine nucleotide translocase in mitochondrial diseases.Hum Mol Genet. 2008 Dec 15;17(24):4036-44. doi: 10.1093/hmg/ddn306. Epub 2008 Sep 22.
• [18] The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis.Hum Mol Genet. 2010 Aug 15;19(16):3114-23. doi: 10.1093/hmg/ddq214. Epub 2010 May 26.
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• [22] 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.
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