Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAGERJ2)

• DOT Name: Connector enhancer of kinase suppressor of ras 2 (CNKSR2)
• Synonyms: Connector enhancer of KSR 2; CNK homolog protein 2; CNK2
• Gene Name: CNKSR2
• Related Disease:
  Epilepsy
  X-linked complex neurodevelopmental disorder
  Breast cancer
  Breast carcinoma
  Christianson syndrome
  Intellectual disability
  Intellectual disability, X-linked 1
  Intellectual disability, X-linked, syndromic, Houge type
  Invasive ductal breast carcinoma
  Nervous system disease
  Non-syndromic X-linked intellectual disability
  Undetermined early-onset epileptic encephalopathy
  Non-insulin dependent diabetes
• UniProt ID: CNKR2_HUMAN
• PDB ID: 2EAN; 3BS5
• Pfam ID: PF06663 ; PF10534 ; PF00595 ; PF00169 ; PF00536
• Sequence:
  MALIMEPVSKWSPSQVVDWMKGLDDCLQQYIKNFEREKISGDQLLRITHQELEDLGVSRI
  GHQELILEAVDLLCALNYGLETENLKTLSHKLNASAKNLQNFITGRRRSGHYDGRTSRKL
  PNDFLTSVVDLIGAAKSLLAWLDRSPFAAVTDYSVTRNNVIQLCLELTTIVQQDCTVYET
  ENKILHVCKTLSGVCDHIISLSSDPLVSQSAHLEVIQLANIKPSEGLGMYIKSTYDGLHV
  ITGTTENSPADRCKKIHAGDEVIQVNHQTVVGWQLKNLVNALREDPSGVILTLKKRPQSM
  LTSAPALLKNMRWKPLALQPLIPRSPTSSVATPSSTISTPTKRDSSALQDLYIPPPPAEP
  YIPRDEKGNLPCEDLRGHMVGKPVHKGSESPNSFLDQEYRKRFNIVEEDTVLYCYEYEKG
  RSSSQGRRESTPTYGKLRPISMPVEYNWVGDYEDPNKMKRDSRRENSLLRYMSNEKIAQE
  EYMFQRNSKKDTGKKSKKKGDKSNSPTHYSLLPSLQMDALRQDIMGTPVPETTLYHTFQQ
  SSLQHKSKKKNKGPIAGKSKRRISCKDLGRGDCEGWLWKKKDAKSYFSQKWKKYWFVLKD
  ASLYWYINEEDEKAEGFISLPEFKIDRASECRKKYAFKACHPKIKSFYFAAEHLDDMNRW
  LNRINMLTAGYAERERIKQEQDYWSESDKEEADTPSTPKQDSPPPPYDTYPRPPSMSCAS
  PYVEAKHSRLSSTETSQSQSSHEEFRQEVTGSSAVSPIRKTASQRRSWQDLIETPLTSSG
  LHYLQTLPLEDSVFSDSAAISPEHRRQSTLPTQKCHLQDHYGPYPLAESERMQVLNGNGG
  KPRSFTLPRDSGFNHCCLNAPVSACDPQDDVQPPEVEEEEEEEEEEGEAAGENIGEKSES
  REEKLGDSLQDLYRALEQASLSPLGEHRISTKMEYKLSFIKRCNDPVMNEKLHRLRILKS
  TLKAREGEVAIIDKVLDNPDLTSKEFQQWKQMYLDLFLDICQNTTSNDPLSISSEVDVIT
  SSLAHTHSYIETHV
• Function: May function as an adapter protein or regulator of Ras signaling pathways.
• Reactome Pathway:
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  MAP2K and MAPK activation (R-HSA-5674135)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Christianson syndrome	DISG6Y6W	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[5]
Intellectual disability, X-linked, syndromic, Houge type	DIS4BX24	Strong	X-linked	[6]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[3]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[7]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[5]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[7]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[8]

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 Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[16]
Permethrin	DMZ0Q1G	Approved	Permethrin affects the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[17]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[16]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Connector enhancer of kinase suppressor of ras 2 (CNKSR2).	[23]

References

• [1] A de novo variant in the X-linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient.Mol Genet Genomic Med. 2019 Oct;7(10):e00861. doi: 10.1002/mgg3.861. Epub 2019 Aug 15.
• [2] 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.
• [3] Regulation of CNKSR2 protein stability by the HECT E3 ubiquitin ligase Smurf2, and its role in breast cancer progression.BMC Cancer. 2018 Mar 13;18(1):284. doi: 10.1186/s12885-018-4188-x.
• [4] Electrical status epilepticus in sleep, a constitutive feature of Christianson syndrome?.Eur J Paediatr Neurol. 2018 Nov;22(6):1124-1132. doi: 10.1016/j.ejpn.2018.07.004. Epub 2018 Jul 21.
• [5] X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.
• [6] Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability. Mol Syndromol. 2012 Jan;2(2):60-63. doi: 10.1159/000335159. Epub 2011 Dec 20.
• [7] Absent CNKSR2 causes seizures and intellectual, attention, and language deficits. Ann Neurol. 2014 Nov;76(5):758-64. doi: 10.1002/ana.24274. Epub 2014 Oct 4.
• [8] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [9] 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.
• [10] 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.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] 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.
• [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] 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.
• [23] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.