Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB1BS0X)

• DOT Name: Kv channel-interacting protein 4 (KCNIP4)
• Synonyms: KChIP4; A-type potassium channel modulatory protein 4; Calsenilin-like protein; Potassium channel-interacting protein 4
• Gene Name: KCNIP4
• Related Disease:
  Attention deficit hyperactivity disorder
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Exocrine pancreatic insufficiency
  Herpes simplex infection
  Neoplasm
  Parkinson disease
  Renal cell carcinoma
  Arrhythmia
  Asthma
• UniProt ID: KCIP4_HUMAN
• Pfam ID: PF13499 ; PF13833
• Sequence:
  MNVRRVESISAQLEEASSTGGFLYAQNSTKRSIKERLMKLLPCSAAKTSSPAIQNSVEDE
  LEMATVRHRPEALELLEAQSKFTKKELQILYRGFKNECPSGVVNEETFKEIYSQFFPQGD
  STTYAHFLFNAFDTDHNGAVSFEDFIKGLSILLRGTVQEKLNWAFNLYDINKDGYITKEE
  MLDIMKAIYDMMGKCTYPVLKEDAPRQHVETFFQKMDKNKDGVVTIDEFIESCQKDENIM
  RSMQLFENVI
• Function: Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. Modulates KCND2 channel density, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. Modulates KCND3/Kv4.3 currents. Isoform 4 does not increase KCND2 expression at the cell membrane. Isoform 4 retains KCND3 in the endoplasmic reticulum and negatively regulates its expression at the cell membrane.
• Tissue Specificity: Predominantly expressed in brain.
• Reactome Pathway: Phase 1 - inactivation of fast Na+ channels (R-HSA-5576894)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Genetic Variation	[2]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[2]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[2]
Exocrine pancreatic insufficiency	DISCZYU2	Strong	Biomarker	[3]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[6]
Arrhythmia	DISFF2NI	Limited	Biomarker	[7]
Asthma	DISW9QNS	Limited	Genetic Variation	[8]

9 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 Kv channel-interacting protein 4 (KCNIP4).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kv channel-interacting protein 4 (KCNIP4).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kv channel-interacting protein 4 (KCNIP4).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kv channel-interacting protein 4 (KCNIP4).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Kv channel-interacting protein 4 (KCNIP4).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Kv channel-interacting protein 4 (KCNIP4).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Kv channel-interacting protein 4 (KCNIP4).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Kv channel-interacting protein 4 (KCNIP4).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kv channel-interacting protein 4 (KCNIP4).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Kv channel-interacting protein 4 (KCNIP4).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Kv channel-interacting protein 4 (KCNIP4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Kv channel-interacting protein 4 (KCNIP4).	[18]

References

• [1] KCNIP4 as a candidate gene for personality disorders and adult ADHD.Eur Neuropsychopharmacol. 2013 Jun;23(6):436-47. doi: 10.1016/j.euroneuro.2012.07.017. Epub 2012 Sep 14.
• [2] Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.Oncotarget. 2017 Oct 9;8(58):98623-98634. doi: 10.18632/oncotarget.21697. eCollection 2017 Nov 17.
• [3] Pancreatic Insufficiency in Cystic Fibrosis: Influence of Inflammatory Response Genes.Pancreas. 2018 Jan;47(1):99-109. doi: 10.1097/MPA.0000000000000963.
• [4] Identification of the transcriptional regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors.Cancer Res. 2001 May 15;61(10):3969-77.
• [5] PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease.Neurology. 2015 Mar 10;84(10):972-80. doi: 10.1212/WNL.0000000000001332. Epub 2015 Feb 6.
• [6] Mapping of constitutional translocation breakpoints in renal cell cancer patients: identification of KCNIP4 as a candidate gene.Cancer Genet Cytogenet. 2007 Nov;179(1):11-8. doi: 10.1016/j.cancergencyto.2007.07.005.
• [7] Whole-Genome Cardiac DNA Methylation Fingerprint and Gene Expression Analysis Provide New Insights in the Pathogenesis of Chronic Chagas Disease Cardiomyopathy.Clin Infect Dis. 2017 Oct 1;65(7):1103-1111. doi: 10.1093/cid/cix506.
• [8] Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene.PLoS One. 2013;8(2):e56179. doi: 10.1371/journal.pone.0056179. Epub 2013 Feb 14.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [17] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.