Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFXDZ3R)

• DOT Name: Forkhead box protein K2 (FOXK2)
• Synonyms: G/T-mismatch specific binding protein; nGTBP; Interleukin enhancer-binding factor 1
• Gene Name: FOXK2
• Related Disease:
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  Hyperglycemia
  Non-small-cell lung cancer
  Stroke
  Type-1/2 diabetes
  Clear cell renal carcinoma
  Neoplasm
  Renal cell carcinoma
  Advanced cancer
  Conduct disorder
  Gastric cancer
  Stomach cancer
• UniProt ID: FOXK2_HUMAN
• PDB ID: 1JXS; 2C6Y
• Pfam ID: PF00498 ; PF00250
• Sequence:
  MAAAAAALSGAGTPPAGGGAGGGGAGGGGSPPGGWAVARLEGREFEYLMKKRSVTIGRNS
  SQGSVDVSMGHSSFISRRHLEIFTPPGGGGHGGAAPELPPAQPRPDAGGDFYLRCLGKNG
  VFVDGVFQRRGAPPLQLPRVCTFRFPSTNIKITFTALSSEKREKQEASESPVKAVQPHIS
  PLTINIPDTMAHLISPLPSPTGTISAANSCPSSPRGAGSSGYKVGRVMPSDLNLMADNSQ
  PENEKEASGGDSPKDDSKPPYSYAQLIVQAITMAPDKQLTLNGIYTHITKNYPYYRTADK
  GWQNSIRHNLSLNRYFIKVPRSQEEPGKGSFWRIDPASESKLIEQAFRKRRPRGVPCFRT
  PLGPLSSRSAPASPNHAGVLSAHSSGAQTPESLSREGSPAPLEPEPGAAQPKLAVIQEAR
  FAQSAPGSPLSSQPVLITVQRQLPQAIKPVTYTVATPVTTSTSQPPVVQTVHVVHQIPAV
  SVTSVAGLAPANTYTVSGQAVVTPAAVLAPPKAEAQENGDHREVKVKVEPIPAIGHATLG
  TASRIIQTAQTTPVQTVTIVQQAPLGQHQLPIKTVTQNGTHVASVPTAVHGQVNNAAASP
  LHMLATHASASASLPTKRHNGDQPEQPELKRIKTEDGEGIVIALSVDTPPAAVREKGVQN
• Function: Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis and autophagy. Recognizes and binds the forkhead DNA sequence motif (5'-GTAAACA-3') and can both act as a transcription activator or repressor, depending on the context. Together with FOXK1, acts as a key regulator of metabolic reprogramming towards aerobic glycolysis, a process in which glucose is converted to lactate in the presence of oxygen. Acts by promoting expression of enzymes for glycolysis (such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR) and lactate dehydrogenase), while suppressing further oxidation of pyruvate in the mitochondria by up-regulating pyruvate dehydrogenase kinases PDK1 and PDK4. Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate. Together with FOXK1, acts as a negative regulator of autophagy in skeletal muscle: in response to starvation, enters the nucleus, binds the promoters of autophagy genes and represses their expression, preventing proteolysis of skeletal muscle proteins. In addition to the 5'-GTAAACA-3' DNA motif, also binds the 5'-TGANTCA-3' palindromic DNA motif, and co-associates with JUN/AP-1 to activate transcription. Also able to bind to a minimal DNA heteroduplex containing a G/T-mismatch with 5'-TRT[G/T]NB-3' sequence. Binds to NFAT-like motifs (purine-rich) in the IL2 promoter. Positively regulates WNT/beta-catenin signaling by translocating DVL proteins into the nucleus. Also binds to HIV-1 long terminal repeat. May be involved in both positive and negative regulation of important viral and cellular promoter elements.
• Tissue Specificity: Expressed in both lymphoid and non-lymphoid cells.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: UCH proteinases (R-HSA-5689603)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Stroke	DISX6UHX	Strong	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Conduct disorder	DISOLUZ1	Limited	Biomarker	[9]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[10]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[10]

6 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 Forkhead box protein K2 (FOXK2).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Forkhead box protein K2 (FOXK2).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Forkhead box protein K2 (FOXK2).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Forkhead box protein K2 (FOXK2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Forkhead box protein K2 (FOXK2).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Forkhead box protein K2 (FOXK2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Forkhead box protein K2 (FOXK2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Forkhead box protein K2 (FOXK2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Forkhead box protein K2 (FOXK2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Forkhead box protein K2 (FOXK2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Forkhead box protein K2 (FOXK2).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Forkhead box protein K2 (FOXK2).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Forkhead box protein K2 (FOXK2).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Forkhead box protein K2 (FOXK2).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Forkhead box protein K2 (FOXK2).	[21]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Forkhead box protein K2 (FOXK2).	[22]
Etretinate	DM2CZFA	Approved	Etretinate increases the expression of Forkhead box protein K2 (FOXK2).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Forkhead box protein K2 (FOXK2).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Forkhead box protein K2 (FOXK2).	[26]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Forkhead box protein K2 (FOXK2).	[28]

References

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• [2] Forkhead box K2 inhibits the proliferation, migration, and invasion of human glioma cells and predicts a favorable prognosis.Onco Targets Ther. 2018 Feb 27;11:1067-1075. doi: 10.2147/OTT.S157126. eCollection 2018.
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• [9] Altered White-Matter Microstructure in Conduct Disorder Is Specifically Associated with Elevated Callous-Unemotional Traits.J Abnorm Child Psychol. 2018 Oct;46(7):1451-1466. doi: 10.1007/s10802-017-0375-5.
• [10] Downregulation of FOXK2 is associated with poor prognosis in patients with gastric cancer.Mol Med Rep. 2018 Nov;18(5):4356-4364. doi: 10.3892/mmr.2018.9466. Epub 2018 Sep 7.
• [11] 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.
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• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
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• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] 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.
• [19] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [23] Gene-specific TCDD suppression of RARalpha- and RXR-mediated induction of tissue transglutaminase. Toxicol Sci. 2002 Jul;68(1):102-8. doi: 10.1093/toxsci/68.1.102.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [26] 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.
• [27] 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.
• [28] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [29] 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.