Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK6971C)

DOT Name	Transcriptional enhancer factor TEF-1 (TEAD1)
Synonyms	NTEF-1; Protein GT-IIC; TEA domain family member 1; TEAD-1; Transcription factor 13; TCF-13
Gene Name	TEAD1
Related Disease	Choriocarcinoma ( ) Hepatocellular carcinoma ( ) leukaemia ( ) Leukemia ( ) Lung cancer ( ) Lung carcinoma ( ) Matthew-Wood syndrome ( ) Adult glioblastoma ( ) B-cell neoplasm ( ) Bladder cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Cardiac failure ( ) Childhood acute lymphoblastic leukemia ( ) Colorectal carcinoma ( ) Congestive heart failure ( ) Dilated cardiomyopathy ( ) Dilated cardiomyopathy 1A ( ) Endometrial cancer ( ) Endometrial carcinoma ( ) Epithelial ovarian cancer ( ) Glioblastoma multiforme ( ) Glioma ( ) Helicoid peripapillary chorioretinal degeneration ( ) Myocardial ischemia ( ) Non-small-cell lung cancer ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Pancreatic cancer ( ) Plasma cell myeloma ( ) Prostate neoplasm ( ) Schizophrenia ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Amyotrophic lateral sclerosis ( ) Gastric cancer ( ) Prostate cancer ( ) Prostate carcinoma ( ) Stomach cancer ( ) Stroke ( ) Triple negative breast cancer ( ) Advanced cancer ( ) Aicardi syndrome ( ) Bone osteosarcoma ( ) Chronic kidney disease ( ) Chronic renal failure ( ) Melanoma ( ) Osteosarcoma ( ) Pancreatic ductal carcinoma ( )
UniProt ID	TEAD1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2HZD; 3KYS; 4RE1; 4Z8E; 5NNX; 6HIL; 6IM5; 7CMM; 7ZJP; 8Q68
Pfam ID	PF01285 ; PF17725
Sequence	MEPSSWSGSESPAENMERMSDSADKPIDNDAEGVWSPDIEQSFQEALAIYPPCGRRKIIL SDEGKMYGRNELIARYIKLRTGKTRTRKQVSSHIQVLARRKSRDFHSKLKDQTAKDKALQ HMAAMSSAQIVSATAIHNKLGLPGIPRPTFPGAPGFWPGMIQTGQPGSSQDVKPFVQQAY PIQPAVTAPIPGFEPASAPAPSVPAWQGRSIGTTKLRLVEFSAFLEQQRDPDSYNKHLFV HIGHANHSYSDPLLESVDIRQIYDKFPEKKGGLKELFGKGPQNAFFLVKFWADLNCNIQD DAGAFYGVTSQYESSENMTVTCSTKVCSFGKQVVEKVETEYARFENGRFVYRINRSPMCE YMINFIHKLKHLPEKYMMNSVLENFTILLVVTNRDTQETLLCMACVFEVSNSEHGAQHHI YRLVKD
Function	Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and cooperatively to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription in vivo in a cell-specific manner. The activation function appears to be mediated by a limiting cell-specific transcriptional intermediary factor (TIF). Involved in cardiac development. Binds to the M-CAT motif.
Tissue Specificity	Preferentially expressed in skeletal muscle. Lower levels in pancreas, placenta, and heart.
KEGG Pathway	Hippo sig.ling pathway (hsa04390 ) Hippo sig.ling pathway - multiple species (hsa04392 )
Reactome Pathway	RUNX3 regulates YAP1-mediated transcription (R-HSA-8951671 ) EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665 ) YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Choriocarcinoma	DISDBVNL	Definitive	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[2]
leukaemia	DISS7D1V	Definitive	Biomarker	[3]
Leukemia	DISNAKFL	Definitive	Biomarker	[3]
Lung cancer	DISCM4YA	Definitive	Genetic Variation	[4]
Lung carcinoma	DISTR26C	Definitive	Genetic Variation	[4]
Matthew-Wood syndrome	DISA7HR7	Definitive	Biomarker	[5]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[6]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[7]
Bladder cancer	DISUHNM0	Strong	Biomarker	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Cardiac failure	DISDC067	Strong	Altered Expression	[10]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[10]
Dilated cardiomyopathy	DISX608J	Strong	Genetic Variation	[12]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[13]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[14]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[14]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[15]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Genetic Variation	[4]
Helicoid peripapillary chorioretinal degeneration	DISFSS5N	Strong	Autosomal dominant	[16]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[15]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[15]
Pancreatic cancer	DISJC981	Strong	Biomarker	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[18]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[19]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[20]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[8]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[8]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Altered Expression	[21]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[22]
Prostate cancer	DISF190Y	moderate	Altered Expression	[23]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[23]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[22]
Stroke	DISX6UHX	moderate	Genetic Variation	[24]
Triple negative breast cancer	DISAMG6N	moderate	Biomarker	[25]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[26]
Aicardi syndrome	DISBQXZB	Limited	Autosomal dominant	[16]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[27]
Chronic kidney disease	DISW82R7	Limited	Biomarker	[28]
Chronic renal failure	DISGG7K6	Limited	Biomarker	[28]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[29]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[27]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[30]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	Transcriptional enhancer factor TEF-1 (TEAD1) decreases the response to substance of Capecitabine.	[43]
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9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[31]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[33]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[35]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[38]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcriptional enhancer factor TEF-1 (TEAD1).	[41]
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⏷ Show the Full List of 9 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcriptional enhancer factor TEF-1 (TEAD1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcriptional enhancer factor TEF-1 (TEAD1).	[40]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transcriptional enhancer factor TEF-1 (TEAD1).	[42]
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References

1	Human chorionic somatomammotropin enhancer function is mediated by cooperative binding of TEF-1 and CSEF-1 to multiple, low-affinity binding sites.Mol Endocrinol. 1997 Aug;11(9):1223-32. doi: 10.1210/mend.11.9.9984.
2	Transcriptional Up-Regulation of APE1/Ref-1 in Hepatic Tumor: Role in Hepatocytes Resistance to Oxidative Stress and Apoptosis.PLoS One. 2015 Dec 1;10(12):e0143289. doi: 10.1371/journal.pone.0143289. eCollection 2015.
3	Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia.Mol Cancer Ther. 2017 Jul;16(7):1401-1411. doi: 10.1158/1535-7163.MCT-17-0099. Epub 2017 Apr 26.
4	A genetic variant in the APE1/Ref-1 gene promoter -141T/G may modulate risk of glioblastoma in a Chinese Han population.BMC Cancer. 2011 Mar 23;11:104. doi: 10.1186/1471-2407-11-104.
5	Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival.Sci Rep. 2018 Sep 13;8(1):13759. doi: 10.1038/s41598-018-32034-9.
6	Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma.Nat Commun. 2018 Oct 1;9(1):4020. doi: 10.1038/s41467-018-06258-2.
7	Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis.J Clin Endocrinol Metab. 2016 Apr;101(4):1552-61. doi: 10.1210/jc.2016-1120. Epub 2016 Mar 15.
8	Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer.Mol Cancer Ther. 2019 Nov;18(11):1947-1960. doi: 10.1158/1535-7163.MCT-18-1166. Epub 2019 Aug 14.
9	A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer.Mol Cell. 2019 Aug 22;75(4):791-806.e8. doi: 10.1016/j.molcel.2019.06.010. Epub 2019 Jul 11.
10	Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte Dedifferentiation During Pressure Overload.Circ Res. 2019 Jan 18;124(2):292-305. doi: 10.1161/CIRCRESAHA.118.314048.
11	TEAD1 enhances proliferation via activating SP1 in colorectal cancer.Biomed Pharmacother. 2016 Oct;83:496-501. doi: 10.1016/j.biopha.2016.06.058. Epub 2016 Jul 18.
12	Tead1 is required for perinatal cardiomyocyte proliferation.PLoS One. 2019 Feb 27;14(2):e0212017. doi: 10.1371/journal.pone.0212017. eCollection 2019.
13	Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy.Exp Mol Pathol. 2017 Dec;103(3):267-275. doi: 10.1016/j.yexmp.2017.11.006. Epub 2017 Nov 15.
14	Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer.Sci Rep. 2017 Jan 10;7:37049. doi: 10.1038/srep37049.
15	Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor.Int J Oncol. 2009 Nov;35(5):1069-79.
16	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.
17	Soy isoflavones augment radiation effect by inhibiting APE1/Ref-1 DNA repair activity in non-small cell lung cancer.J Thorac Oncol. 2011 Apr;6(4):688-98. doi: 10.1097/JTO.0b013e31821034ae.
18	Elevated expression of APE1/Ref-1 and its regulation on IL-6 and IL-8 in bone marrow stromal cells of multiple myeloma.Clin Lymphoma Myeloma Leuk. 2010 Oct;10(5):385-93. doi: 10.3816/CLML.2010.n.072.
19	TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer.Br J Cancer. 2008 Dec 2;99(11):1849-58. doi: 10.1038/sj.bjc.6604774. Epub 2008 Nov 11.
20	Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
21	Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies.Acta Neuropathol Commun. 2019 Apr 29;7(1):65. doi: 10.1186/s40478-019-0710-x.
22	TEAD1/4 exerts oncogenic role and is negatively regulated by miR-4269 in gastric tumorigenesis.Oncogene. 2017 Nov 23;36(47):6518-6530. doi: 10.1038/onc.2017.257. Epub 2017 Jul 31.
23	ZNFX1 anti-sense RNA 1 promotes the tumorigenesis of prostate cancer by regulating c-Myc expression via a regulatory network of competing endogenous RNAs.Cell Mol Life Sci. 2020 Mar;77(6):1135-1152. doi: 10.1007/s00018-019-03226-x. Epub 2019 Jul 18.
24	A prospective study of polymorphisms of DNA repair genes XRCC1, XPD23 and APE/ref-1 and risk of stroke in Linxian, China.J Epidemiol Community Health. 2007 Aug;61(8):737-41. doi: 10.1136/jech.2006.048934.
25	Therapeutic positioning of secretory acetylated APE1/Ref-1 requirement for suppression of tumor growth in triple-negative breast cancer in vivo.Sci Rep. 2018 Jun 7;8(1):8701. doi: 10.1038/s41598-018-27025-9.
26	Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1).Bioorg Med Chem. 2017 May 1;25(9):2531-2544. doi: 10.1016/j.bmc.2017.01.028. Epub 2017 Jan 21.
27	TEAD1 mediates the oncogenic activities of Hippo-YAP1 signaling in osteosarcoma.Biochem Biophys Res Commun. 2017 Jun 24;488(2):297-302. doi: 10.1016/j.bbrc.2017.05.032. Epub 2017 May 5.
28	Economic Issues of Chronic Kidney Disease and End-Stage Renal Disease.Contrib Nephrol. 2019;198:87-93. doi: 10.1159/000496533. Epub 2019 Apr 16.
29	Genetic variants in Hippo pathway genes YAP1, TEAD1 and TEAD4 are associated with melanoma-specific survival.Int J Cancer. 2015 Aug 1;137(3):638-45. doi: 10.1002/ijc.29429. Epub 2015 Jan 28.
30	APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma - characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing.Mol Oncol. 2017 Dec;11(12):1711-1732. doi: 10.1002/1878-0261.12138. Epub 2017 Oct 19.
31	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
32	Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
33	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
34	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.
35	Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
36	THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
37	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.
38	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.
39	Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
40	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.
41	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.
42	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.
43	Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.