Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSNAEQ9)

• DOT Name: Connector enhancer of kinase suppressor of ras 1 (CNKSR1)
• Synonyms: Connector enhancer of KSR 1; CNK homolog protein 1; CNK1; hCNK1; Connector enhancer of KSR-like
• Gene Name: CNKSR1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Epilepsy
  Pancreatic cancer
  Neoplasm
  Intellectual disability
• UniProt ID: CNKR1_HUMAN
• PDB ID: 1WWV
• Pfam ID: PF10534 ; PF00169
• Sequence:
  MEPVETWTPGKVATWLRGLDDSLQDYPFEDWQLPGKNLLQLCPQSLEALAVRSLGHQELI
  LGGVEQLQALSSRLQTENLQSLTEGLLGATHDFQSIVQGCLGDCAKTPIDVLCAAVELLH
  EADALLFWLSRYLFSHLNDFSACQEIRDLLEELSQVLHEDGPAAEKEGTVLRICSHVAGI
  CHNILVCCPKELLEQKAVLEQVQLDSPLGLEIHTTSNCQHFVSQVDTQVPTDSRLQIQPG
  DEVVQINEQVVVREERDMVGWPRKNMVRELLREPAGLSLVLKKIPIPETPPQTPPQVLDS
  PHQRSPSLSLAPLSPRAPSEDVFAFDLSSNPSPGPSPAWTDSASLGPEPLPIPPEPPAIL
  PAGVAGTPGLPESPDKSPVGRKKSKGLATRLSRRRVSCRELGRPDCDGWLLLRKAPGGFM
  GPRWRRRWFVLKGHTLYWYRQPQDEKAEGLINVSNYSLESGHDQKKKYVFQLTHDVYKPF
  IFAADTLTDLSMWVRHLITCISKYQSPGRAPPPREEDCYSETEAEDPDDEAGSHSASPSP
  AQAGSPLHGDTSPAATPTQRSPRTSFGSLTDSSEEALEGMVRGLRQGGVSLLGQPQPLTQ
  EQWRSSFMRRNRDPQLNERVHRVRALQSTLKAKLQELQVLEEVLGDPELTGEKFRQWKEQ
  NRELYSEGLGAWGVAQAEGSSHILTSDSTEQSPHSLPSDPEEHSHLCPLTSESSLRPPDL
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Connector enhancer of kinase suppressor of ras 1 (CNKSR1).	[14]

References

• [1] An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors.Cancer Res. 2019 Jun 15;79(12):3100-3111. doi: 10.1158/0008-5472.CAN-18-2372. Epub 2019 Apr 30.
• [2] CNK1 promotes invasion of cancer cells through NF-kappaB-dependent signaling.Mol Cancer Res. 2010 Mar;8(3):395-406. doi: 10.1158/1541-7786.MCR-09-0296. Epub 2010 Mar 2.
• [3] Long-term antiepileptic effects of chronic intake of CNK-602A, a thyrotropin-releasing hormone analogue, on spontaneously epileptic rats.Epilepsia. 1996 Apr;37(4):328-31. doi: 10.1111/j.1528-1157.1996.tb00567.x.
• [4] Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer.BMC Cancer. 2017 Jul 21;17(1):495. doi: 10.1186/s12885-017-3481-4.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] 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.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.