Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ5XLVU)

DOT Name	Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D)
Synonyms	CaM kinase II subunit delta; CaMK-II subunit delta; EC 2.7.11.17
Gene Name	CAMK2D
Related Disease	Arrhythmia ( ) Atrial fibrillation ( ) Cardiac disease ( ) Cardiac failure ( ) Congestive heart failure ( ) Epilepsy ( ) Myocardial ischemia ( ) Non-small-cell lung cancer ( ) Polycystic ovarian syndrome ( ) Familial atrial fibrillation ( ) Epithelial ovarian cancer ( )
UniProt ID	KCC2D_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2VN9; 2W2C; 2WEL; 3GP2; 5VLO; 6AYW; 7ZRP; 7ZRQ
EC Number	2.7.11.17
Pfam ID	PF08332 ; PF00069
Sequence	MASTTTCTRFTDEYQLFEELGKGAFSVVRRCMKIPTGQEYAAKIINTKKLSARDHQKLER EARICRLLKHPNIVRLHDSISEEGFHYLVFDLVTGGELFEDIVAREYYSEADASHCIQQI LESVNHCHLNGIVHRDLKPENLLLASKSKGAAVKLADFGLAIEVQGDQQAWFGFAGTPGY LSPEVLRKDPYGKPVDMWACGVILYILLVGYPPFWDEDQHRLYQQIKAGAYDFPSPEWDT VTPEAKDLINKMLTINPAKRITASEALKHPWICQRSTVASMMHRQETVDCLKKFNARRKL KGAILTTMLATRNFSAAKSLLKKPDGVKESTESSNTTIEDEDVKARKQEIIKVTEQLIEA INNGDFEAYTKICDPGLTAFEPEALGNLVEGMDFHRFYFENALSKSNKPIHTIILNPHVH LVGDDAACIAYIRLTQYMDGSGMPKTMQSEETRVWHRRDGKWQNVHFHRSGSPTVPIKPP CIPNGKENFSGGTSLWQNI
Function	Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling factor. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway.
Tissue Specificity	Expressed in cardiac muscle and skeletal muscle. Isoform Delta 3, isoform Delta 2, isoform Delta 8 and isoform Delta 9 are expressed in cardiac muscle. Isoform Delta 11 is expressed in skeletal muscle.
KEGG Pathway	ErbB sig.ling pathway (hsa04012 ) Calcium sig.ling pathway (hsa04020 ) cAMP sig.ling pathway (hsa04024 ) HIF-1 sig.ling pathway (hsa04066 ) Oocyte meiosis (hsa04114 ) Efferocytosis (hsa04148 ) Necroptosis (hsa04217 ) Adrenergic sig.ling in cardiomyocytes (hsa04261 ) Wnt sig.ling pathway (hsa04310 ) Axon guidance (hsa04360 ) Circadian entrainment (hsa04713 ) Long-term potentiation (hsa04720 ) Neurotrophin sig.ling pathway (hsa04722 ) Cholinergic sy.pse (hsa04725 ) Dopaminergic sy.pse (hsa04728 ) Olfactory transduction (hsa04740 ) Inflammatory mediator regulation of TRP channels (hsa04750 ) Insulin secretion (hsa04911 ) GnRH sig.ling pathway (hsa04912 ) Melanogenesis (hsa04916 ) Oxytocin sig.ling pathway (hsa04921 ) Glucagon sig.ling pathway (hsa04922 ) Aldosterone synthesis and secretion (hsa04925 ) Cushing syndrome (hsa04934 ) Gastric acid secretion (hsa04971 ) Parkinson disease (hsa05012 ) Pathways of neurodegeneration - multiple diseases (hsa05022 ) Amphetamine addiction (hsa05031 ) Tuberculosis (hsa05152 ) Pathways in cancer (hsa05200 ) Proteoglycans in cancer (hsa05205 ) Glioma (hsa05214 ) Diabetic cardiomyopathy (hsa05415 ) Lipid and atherosclerosis (hsa05417 )
Reactome Pathway	HSF1-dependent transactivation (R-HSA-3371571 ) Trafficking of AMPA receptors (R-HSA-399719 ) Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066 ) Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982 ) Phase 0 - rapid depolarisation (R-HSA-5576892 ) Ion homeostasis (R-HSA-5578775 ) RAF activation (R-HSA-5673000 ) RAF/MAP kinase cascade (R-HSA-5673001 ) Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946 ) Signaling by BRAF and RAF1 fusions (R-HSA-6802952 ) Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955 ) Interferon gamma signaling (R-HSA-877300 ) Regulation of MECP2 expression and activity (R-HSA-9022692 ) Ion transport by P-type ATPases (R-HSA-936837 ) Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736 ) Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324 ) Long-term potentiation (R-HSA-9620244 ) Signaling downstream of RAS mutants (R-HSA-9649948 ) Signaling by RAF1 mutants (R-HSA-9656223 ) CaMK IV-mediated phosphorylation of CREB (R-HSA-111932 )

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Arrhythmia	DISFF2NI	Strong	Biomarker	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Cardiac disease	DISVO1I5	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[6]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[7]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[8]
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⏷ Show the Full List of 11 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[18]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[21]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[27]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[28]
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⏷ Show the Full List of 19 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D).	[25]
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References

1	Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.J Mol Cell Cardiol. 2018 Dec;125:18-28. doi: 10.1016/j.yjmcc.2018.10.010. Epub 2018 Oct 12.
2	Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
3	Compromised cardiovascular function in aged rats corresponds with increased expression and activity of calcium/calmodulin dependent protein kinase II in aortic endothelium.Vascul Pharmacol. 2019 Jul-Aug;118-119:106560. doi: 10.1016/j.vph.2019.04.002. Epub 2019 Apr 30.
4	Polymorphisms in CACNA1E and Camk2d are associated with seizure susceptibility of Sprague-Dawley rats.Epilepsy Res. 2010 Sep;91(1):28-34. doi: 10.1016/j.eplepsyres.2010.06.006. Epub 2010 Jul 16.
5	Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
6	Genome-wide association study of survival in early-stage non-small cell lung cancer.Ann Surg Oncol. 2015 Feb;22(2):630-5. doi: 10.1245/s10434-014-3983-0. Epub 2014 Aug 22.
7	Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
8	Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1131-45. doi: 10.1158/1055-9965.EPI-10-1224. Epub 2011 Mar 29.
9	Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
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	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.
12	Influence of Iron on Cytotoxicity and Gene Expression Profiles Induced by Arsenic in HepG2 Cells. Int J Environ Res Public Health. 2019 Nov 14;16(22):4484. doi: 10.3390/ijerph16224484.
13	The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
14	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
15	Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
16	Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
17	Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
18	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
19	Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
20	Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
21	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.
22	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
23	Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
24	Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
25	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.
26	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
27	Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
28	Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.