Details of Drug Off-Target (DOT)

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

• DOT Name: ATP-binding cassette sub-family C member 9 (ABCC9)
• Synonyms: Sulfonylurea receptor 2
• Gene Name: ABCC9
• Related Disease:
  Hypertrichotic osteochondrodysplasia Cantu type
  Dilated cardiomyopathy 1O
  Acromegaloid facial appearance syndrome
  Hirsutism
  Obsolete familial isolated dilated cardiomyopathy
  Atrial fibrillation, familial, 12
  Brugada syndrome
  Dilated cardiomyopathy
  Intellectual disability and myopathy syndrome
• UniProt ID: ABCC9_HUMAN
• Pfam ID: PF00664 ; PF00005
• Sequence:
  MSLSFCGNNISSYNINDGVLQNSCFVDALNLVPHVFLLFITFPILFIGWGSQSSKVQIHH
  NTWLHFPGHNLRWILTFALLFVHVCEIAEGIVSDSRRESRHLHLFMPAVMGFVATTTSIV
  YYHNIETSNFPKLLLALFLYWVMAFITKTIKLVKYCQSGLDISNLRFCITGMMVILNGLL
  MAVEINVIRVRRYVFFMNPQKVKPPEDLQDLGVRFLQPFVNLLSKATYWWMNTLIISAHK
  KPIDLKAIGKLPIAMRAVTNYVCLKDAYEEQKKKVADHPNRTPSIWLAMYRAFGRPILLS
  STFRYLADLLGFAGPLCISGIVQRVNETQNGTNNTTGISETLSSKEFLENAYVLAVLLFL
  ALILQRTFLQASYYVTIETGINLRGALLAMIYNKILRLSTSNLSMGEMTLGQINNLVAIE
  TNQLMWFLFLCPNLWAMPVQIIMGVILLYNLLGSSALVGAAVIVLLAPIQYFIATKLAEA
  QKSTLDYSTERLKKTNEILKGIKLLKLYAWEHIFCKSVEETRMKELSSLKTFALYTSLSI
  FMNAAIPIAAVLATFVTHAYASGNNLKPAEAFASLSLFHILVTPLFLLSTVVRFAVKAII
  SVQKLNEFLLSDEIGDDSWRTGESSLPFESCKKHTGVQPKTINRKQPGRYHLDSYEQSTR
  RLRPAETEDIAIKVTNGYFSWGSGLATLSNIDIRIPTGQLTMIVGQVGCGKSSLLLAILG
  EMQTLEGKVHWSNVNESEPSFEATRSRNRYSVAYAAQKPWLLNATVEENITFGSPFNKQR
  YKAVTDACSLQPDIDLLPFGDQTEIGERGINLSGGQRQRICVARALYQNTNIVFLDDPFS
  ALDIHLSDHLMQEGILKFLQDDKRTLVLVTHKLQYLTHADWIIAMKDGSVLREGTLKDIQ
  TKDVELYEHWKTLMNRQDQELEKDMEADQTTLERKTLRRAMYSREAKAQMEDEDEEEEEE
  EDEDDNMSTVMRLRTKMPWKTCWRYLTSGGFFLLILMIFSKLLKHSVIVAIDYWLATWTS
  EYSINNTGKADQTYYVAGFSILCGAGIFLCLVTSLTVEWMGLTAAKNLHHNLLNKIILGP
  IRFFDTTPLGLILNRFSADTNIIDQHIPPTLESLTRSTLLCLSAIGMISYATPVFLVALL
  PLGVAFYFIQKYFRVASKDLQELDDSTQLPLLCHFSETAEGLTTIRAFRHETRFKQRMLE
  LTDTNNIAYLFLSAANRWLEVRTDYLGACIVLTASIASISGSSNSGLVGLGLLYALTITN
  YLNWVVRNLADLEVQMGAVKKVNSFLTMESENYEGTMDPSQVPEHWPQEGEIKIHDLCVR
  YENNLKPVLKHVKAYIKPGQKVGICGRTGSGKSSLSLAFFRMVDIFDGKIVIDGIDISKL
  PLHTLRSRLSIILQDPILFSGSIRFNLDPECKCTDDRLWEALEIAQLKNMVKSLPGGLDA
  VVTEGGENFSVGQRQLFCLARAFVRKSSILIMDEATASIDMATENILQKVVMTAFADRTV
  VTIAHRVSSIMDAGLVLVFSEGILVECDTVPNLLAHKNGLFSTLVMTNK
• Function: Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation.
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway:
  ABC-family proteins mediated transport (R-HSA-382556)
  Ion homeostasis (R-HSA-5578775)
  Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome (R-HSA-5678420)
  ATP sensitive Potassium channels (R-HSA-1296025)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypertrichotic osteochondrodysplasia Cantu type	DISI9W4I	Definitive	Autosomal dominant	[1]
Dilated cardiomyopathy 1O	DIS5GW01	Strong	Autosomal dominant	[2]
Acromegaloid facial appearance syndrome	DIS6MBD5	Supportive	Autosomal dominant	[3]
Hirsutism	DISCCPCL	Supportive	Autosomal dominant	[3]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[2]
Atrial fibrillation, familial, 12	DISDFYQA	Limited	Unknown	[4]
Brugada syndrome	DISSGN0E	Limited	Autosomal dominant	[5]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[6]
Intellectual disability and myopathy syndrome	DISU9X3F	Limited	Autosomal recessive	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Glimepiride	DM5FSJA	Approved	ATP-binding cassette sub-family C member 9 (ABCC9) increases the Blood glucose decreased ADR of Glimepiride.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[16]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-binding cassette sub-family C member 9 (ABCC9).	[20]

1 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 decreases the methylation of ATP-binding cassette sub-family C member 9 (ABCC9).	[18]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet. 2004 Apr;36(4):382-7. doi: 10.1038/ng1329. Epub 2004 Mar 21.
• [3] Wide clinical variability in conditions with coarse facial features and hypertrichosis caused by mutations in ABCC9. Am J Med Genet A. 2013 Feb;161A(2):295-300. doi: 10.1002/ajmg.a.35735. Epub 2013 Jan 10.
• [4] KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med. 2007 Feb;4(2):110-6. doi: 10.1038/ncpcardio0792.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] 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.
• [7] ABCC9-related Intellectual disability Myopathy Syndrome is a K(ATP) channelopathy with loss-of-function mutations in ABCC9. Nat Commun. 2019 Oct 1;10(1):4457. doi: 10.1038/s41467-019-12428-7.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] 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.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.