Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCQPEM4)

• DOT Name: Calsenilin (KCNIP3)
• Synonyms: A-type potassium channel modulatory protein 3; DRE-antagonist modulator; DREAM; Kv channel-interacting protein 3; KChIP3
• Gene Name: KCNIP3
• Related Disease:
  Neoplasm
  Alzheimer disease
  Analgesia
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Cardiovascular disease
  Cerebral infarction
  CLN2 Batten disease
  Congestive heart failure
  Dementia
  Epilepsy
  Epithelial ovarian cancer
  Familial Alzheimer disease
  Huntington disease
  Leukemia
  Melanoma
  Mental disorder
  Osteoarthritis
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Retinoblastoma
  Sleep disorder
  Variegate porphyria
  Acute myelogenous leukaemia
  Amyotrophic lateral sclerosis
  Gastrointestinal stromal tumour
  Anxiety
  Anxiety disorder
  Dyspepsia
  Advanced cancer
  Asthma
  High blood pressure
  Meningioma
  Neuroblastoma
  Rheumatoid arthritis
• UniProt ID: CSEN_HUMAN
• PDB ID: 2E6W
• Pfam ID: PF13499 ; PF13833
• Sequence:
  MQPAKEVTKASDGSLLGDLGHTPLSKKEGIKWQRPRLSRQALMRCCLVKWILSSTAPQGS
  DSSDSELELSTVRHQPEGLDQLQAQTKFTKKELQSLYRGFKNECPTGLVDEDTFKLIYAQ
  FFPQGDATTYAHFLFNAFDADGNGAIHFEDFVVGLSILLRGTVHEKLKWAFNLYDINKDG
  YITKEEMLAIMKSIYDMMGRHTYPILREDAPAEHVERFFEKMDRNQDGVVTIEEFLEACQ
  KDENIMSSMQLFENVI
• Function: Calcium-dependent transcriptional repressor that binds to the DRE element of genes including PDYN and FOS. Affinity for DNA is reduced upon binding to calcium and enhanced by binding to magnesium. Seems to be involved in nociception; Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels, such as KCND2/Kv4.2 and KCND3/Kv4.3. Modulates channel expression at the cell membrane, gating characteristics, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner; May play a role in the regulation of PSEN2 proteolytic processing and apoptosis. Together with PSEN2 involved in modulation of amyloid-beta formation.
• Tissue Specificity: Highly expressed in brain. Widely expressed at lower levels. Expression levels are elevated in brain cortex regions affected by Alzheimer disease.
• Reactome Pathway:
  Regulation of NPAS4 gene transcription (R-HSA-9768777)
  Phase 1 - inactivation of fast Na+ channels (R-HSA-5576894)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Analgesia	DISK3TVI	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[6]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[7]
CLN2 Batten disease	DISZC5YB	Strong	Genetic Variation	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Dementia	DISXL1WY	Strong	Biomarker	[9]
Epilepsy	DISBB28L	Strong	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[11]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[12]
Huntington disease	DISQPLA4	Strong	Biomarker	[13]
Leukemia	DISNAKFL	Strong	Altered Expression	[14]
Melanoma	DIS1RRCY	Strong	Biomarker	[15]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[16]
Osteoarthritis	DIS05URM	Strong	Biomarker	[17]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[18]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[9]
Variegate porphyria	DIS8OK5W	Strong	Altered Expression	[19]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[20]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[21]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[22]
Anxiety	DISIJDBA	Disputed	Genetic Variation	[23]
Anxiety disorder	DISBI2BT	Disputed	Genetic Variation	[23]
Dyspepsia	DISYEEY6	Disputed	Biomarker	[23]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[24]
Asthma	DISW9QNS	Limited	Biomarker	[25]
High blood pressure	DISY2OHH	Limited	Biomarker	[26]
Meningioma	DISPT4TG	Limited	Biomarker	[1]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[27]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[28]

2 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 Calsenilin (KCNIP3).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Calsenilin (KCNIP3).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Calsenilin (KCNIP3).	[30]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Calsenilin (KCNIP3).	[31]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Calsenilin (KCNIP3).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Calsenilin (KCNIP3).	[34]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Calsenilin (KCNIP3).	[35]
Manganese	DMKT129	Investigative	Manganese increases the expression of Calsenilin (KCNIP3).	[36]

References

• [1] Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors.Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21715-21726. doi: 10.1073/pnas.1912858116. Epub 2019 Oct 7.
• [2] Inhibition of the Neuronal Calcium Sensor DREAM Modulates Presenilin-2 Endoproteolysis.Front Mol Neurosci. 2018 Dec 3;11:449. doi: 10.3389/fnmol.2018.00449. eCollection 2018.
• [3] Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats.Front Mol Neurosci. 2019 Jan 25;12:5. doi: 10.3389/fnmol.2019.00005. eCollection 2019.
• [4] The function of DREAM gene mediated by NF-kB signal pathway in the pathogenesis of osteosarcoma.J BUON. 2017 Jul-Aug;22(4):1068-1072.
• [5] Artificial intelligence in breast imaging.Clin Radiol. 2019 May;74(5):357-366. doi: 10.1016/j.crad.2019.02.006. Epub 2019 Mar 18.
• [6] Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure.Circ Res. 2019 Jul 19;125(3):265-281. doi: 10.1161/CIRCRESAHA.119.314951. Epub 2019 Jul 18.
• [7] Post-treatment with a Hydrogen Sulfide Donor Limits Neuronal Injury and Modulates Potassium Voltage-gated Channel Subfamily D Member 2 (Kv4.2) and Potassium Channel Interacting Protein 3 (KChIP3) During Transient Global Cerebral Ischemia.Curr Neurovasc Res. 2017;14(4):397-405. doi: 10.2174/1567202614666171108113447.
• [8] Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin.Hum Mol Genet. 2007 Feb 1;16(3):317-26. doi: 10.1093/hmg/ddl466. Epub 2006 Dec 22.
• [9] DREAMS-START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives) for people with dementia and sleep disturbances: a single-blind feasibility and acceptability randomized controlled trial.Int Psychogeriatr. 2019 Feb;31(2):251-265. doi: 10.1017/S1041610218000753. Epub 2018 Sep 17.
• [10] Reduced expression of calsenilin/DREAM/KChIP3 in the brains of kainic acid-induced seizure and epilepsy patients.Neurosci Lett. 2003 Apr 3;340(1):33-6. doi: 10.1016/s0304-3940(03)00067-3.
• [11] The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb.Oncogene. 2019 Feb;38(7):1080-1092. doi: 10.1038/s41388-018-0490-y. Epub 2018 Sep 11.
• [12] Calsenilin is a substrate for caspase-3 that preferentially interacts with the familial Alzheimer's disease-associated C-terminal fragment of presenilin 2.J Biol Chem. 2001 Jun 1;276(22):19197-204. doi: 10.1074/jbc.M008597200. Epub 2001 Mar 9.
• [13] Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington's disease treatment.Sci Rep. 2019 May 13;9(1):7260. doi: 10.1038/s41598-019-43677-7.
• [14] Fas signaling and blockade of Bcr-Abl kinase induce apoptotic Hrk protein via DREAM inhibition in human leukemia cells.Haematologica. 2002 Sep;87(9):903-7.
• [15] Neo-DREAM study investigating Daromun for the treatment of clinical stage IIIB/C melanoma.Future Oncol. 2019 Nov;15(32):3665-3674. doi: 10.2217/fon-2019-0433. Epub 2019 Sep 20.
• [16] Integrative approach for inference of gene regulatory networks using lasso-based random featuring and application to psychiatric disorders.BMC Med Genomics. 2016 Aug 10;9 Suppl 2(Suppl 2):50. doi: 10.1186/s12920-016-0202-9.
• [17] DREAM is reduced in synovial fibroblasts of patients with chronic arthritic pain: is it a suitable target for peripheral pain management?.Arthritis Res Ther. 2008;10(3):R60. doi: 10.1186/ar2431. Epub 2008 May 28.
• [18] Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM.Cell Death Differ. 2018 Jan;25(1):114-132. doi: 10.1038/cdd.2017.172. Epub 2017 Nov 10.
• [19] Vasopressin regulates hypothalamic GnRH synthesis: Histomorphological evidence in hypothalamus and biological effects in GT1-7 cells.Life Sci. 2019 Jun 15;227:166-174. doi: 10.1016/j.lfs.2019.04.055. Epub 2019 Apr 23.
• [20] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [21] Stratification of amyotrophic lateral sclerosis patients: a crowdsourcing approach.Sci Rep. 2019 Jan 24;9(1):690. doi: 10.1038/s41598-018-36873-4.
• [22] The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis.Cancer Res. 2013 Aug 15;73(16):5120-9. doi: 10.1158/0008-5472.CAN-13-0579. Epub 2013 Jun 20.
• [23] Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study).Neurogastroenterol Motil. 2018 Jul;30(7):e13319. doi: 10.1111/nmo.13319. Epub 2018 Mar 2.
• [24] Cyclin D-CDK4 relieves cooperative repression of proliferation and cell cycle gene expression by DREAM and RB.Oncogene. 2019 Jun;38(25):4962-4976. doi: 10.1038/s41388-019-0767-9. Epub 2019 Mar 4.
• [25] Asthma Exacerbations Associated with Lung Function Decline in Patients with Severe Eosinophilic Asthma.J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):980-986.e1. doi: 10.1016/j.jaip.2017.12.019. Epub 2018 Feb 15.
• [26] Diagnosing hypertension in Indigenous Canadians (DREAM-GLOBAL): A randomized controlled trial to compare the effectiveness of short message service messaging for management of hypertension: Main results.J Clin Hypertens (Greenwich). 2019 Jan;21(1):29-36. doi: 10.1111/jch.13434. Epub 2018 Nov 26.
• [27] Calsenilin regulates presenilin 1/-secretase-mediated N-cadherin -cleavage and -catenin signaling.FASEB J. 2011 Dec;25(12):4174-83. doi: 10.1096/fj.11-185926. Epub 2011 Aug 18.
• [28] Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis.Nat Commun. 2016 Aug 23;7:12460. doi: 10.1038/ncomms12460.
• [29] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [30] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [31] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [32] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [33] 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.
• [34] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [35] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [36] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.