Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXP4QH8)

• DOT Name: Connector enhancer of kinase suppressor of ras 3 (CNKSR3)
• Synonyms: Connector enhancer of KSR 3; CNK homolog protein 3; CNK3; CNKSR family member 3; Maguin-like protein
• Gene Name: CNKSR3
• Related Disease:
  Adult T-cell leukemia/lymphoma
  Ataxia-telangiectasia
  Diabetic kidney disease
  Diabetic retinopathy
  Focal segmental glomerulosclerosis
  Non-small-cell lung cancer
  Parkinson disease
  T-cell acute lymphoblastic leukaemia
  T-cell leukaemia
  Adenovirus infection
  Melanoma
  Uveal Melanoma
  Human T-lymphotropic virus 1 infectious disease
• UniProt ID: CNKR3_HUMAN
• Pfam ID: PF06663 ; PF10534 ; PF00595 ; PF00536
• Sequence:
  MEPVTKWSPKQVVDWTRGLDDCLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQE
  LVLEAVDLLCALNYGLETDNMKNLVLKLRASSHNLQNYISSRRKSPAYDGNTSRKAPNEF
  LTSVVELIGAAKALLAWLDRAPFTGITDFSVTKNKIIQLCLDLTTTVQKDCFVAEMEDKV
  LTVVKVLNGICDKTIRSTTDPVMSQCACLEEVHLPNIKPGEGLGMYIKSTYDGLHVITGT
  TENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLLKKRPTGSFNFT
  PAPLKNLRWKPPLVQTSPPPATTQSPESTMDTSLKKEKSAILDLYIPPPPAVPYSPRDEN
  GSFVYGGSSKCKQPLPGPKGSESPNSFLDQESRRRRFTIADSDQLPGYSVETNILPTKMR
  EKTPSYGKPRPLSMPADGNWMGIVDPFARPRGHGRKGEDALCRYFSNERIPPIIEESSSP
  PYRFSRPTTERHLVRGADYIRGSRCYINSDLHSSATIPFQEEGTKKKSGSSATKSSSTEP
  SLLVSWFTRLKLLTH
• Function: Involved in transepithelial sodium transport. Regulates aldosterone-induced and epithelial sodium channel (ENaC)-mediated sodium transport through regulation of ENaC cell surface expression. Acts as a scaffold protein coordinating the assembly of an ENaC-regulatory complex (ERC).

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[1]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[2]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[3]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[4]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[7]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[1]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[1]
Adenovirus infection	DISUYSBZ	moderate	Biomarker	[8]
Melanoma	DIS1RRCY	moderate	Biomarker	[9]
Uveal Melanoma	DISA7ZGL	moderate	Altered Expression	[9]
Human T-lymphotropic virus 1 infectious disease	DISN5C4M	Disputed	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[17]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[20]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[21]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[27]

1 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 Connector enhancer of kinase suppressor of ras 3 (CNKSR3).	[26]

References

• [1] MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia.Int J Hematol. 2018 Mar;107(3):337-344. doi: 10.1007/s12185-017-2359-1. Epub 2017 Oct 17.
• [2] Differential gene expression profile in PBMCs from subjects with AERD and ATA: a gene marker for AERD.Mol Genet Genomics. 2012 May;287(5):361-71. doi: 10.1007/s00438-012-0685-9. Epub 2012 Mar 29.
• [3] Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).PLoS Genet. 2015 Aug 25;11(8):e1005352. doi: 10.1371/journal.pgen.1005352. eCollection 2015 Aug.
• [4] Progress in Defining the Genetic Basis of Diabetic Complications.Curr Diab Rep. 2017 Sep;17(9):80. doi: 10.1007/s11892-017-0906-z.
• [5] Up-regulation of the homophilic adhesion molecule sidekick-1 in podocytes contributes to glomerulosclerosis.J Biol Chem. 2010 Aug 13;285(33):25677-85. doi: 10.1074/jbc.M110.133959. Epub 2010 Jun 18.
• [6] Significance of miR-15a-5p and CNKSR3 as Novel Prognostic Biomarkers in Non-Small Cell Lung Cancer.Anticancer Agents Med Chem. 2018;18(12):1695-1701. doi: 10.2174/1871520618666180718100656.
• [7] Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.Ann Neurol. 2012 Mar;71(3):370-84. doi: 10.1002/ana.22687.
• [8] The PDZ1 and PDZ3 domains of MAGI-1 regulate the eight-exon isoform of the coxsackievirus and adenovirus receptor.J Virol. 2012 Sep;86(17):9244-54. doi: 10.1128/JVI.01138-12. Epub 2012 Jun 20.
• [9] Single nucleotide polymorphism array analysis of uveal melanomas reveals that amplification of CNKSR3 is correlated with improved patient survival.Am J Pathol. 2013 Mar;182(3):678-87. doi: 10.1016/j.ajpath.2012.11.036. Epub 2013 Jan 26.
• [10] Human T-cell leukemia virus type 1 Tax protein interacts with and mislocalizes the PDZ domain protein MAGI-1.Cancer Sci. 2013 Mar;104(3):313-20. doi: 10.1111/cas.12087. Epub 2013 Jan 30.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [16] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] 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.
• [20] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [21] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [22] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.