Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT50MRZ1)

• DOT Name: Transducin-like enhancer protein 1 (TLE1)
• Synonyms: E(Sp1) homolog; Enhancer of split groucho-like protein 1; ESG1
• Gene Name: TLE1
• Related Disease:
  B-cell lymphoma
  Carcinoma
  Crohn disease
  leukaemia
  Leukemia
  Acute lymphocytic leukaemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Alzheimer disease
  Breast cancer
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Depression
  Diabetic retinopathy
  Ewing sarcoma
  Lung adenocarcinoma
  Lung cancer
  Lung neoplasm
  Malignant peripheral nerve sheath tumor
  Malignant soft tissue neoplasm
  Melanoma
  Non-insulin dependent diabetes
  Psoriasis
  Sarcoma
  Small-cell lung cancer
  Soft tissue neoplasm
  Squamous cell carcinoma
  T-cell acute lymphoblastic leukaemia
  Adult lymphoma
  Breast carcinoma
  Breast neoplasm
  Lung carcinoma
  Lymphoma
  Pancreatic cancer
  Pediatric lymphoma
  Gastric cancer
  Mesothelioma
  Stomach cancer
  Adult glioblastoma
  Advanced cancer
  Glioblastoma multiforme
  Movement disorder
  Neuroblastoma
  Type-1/2 diabetes
• UniProt ID: TLE1_HUMAN
• PDB ID: 1GXR; 2CE8; 2CE9; 4OM2; 4OM3; 5MWJ
• Pfam ID: PF03920 ; PF00400
• Sequence:
  MFPQSRHPTPHQAAGQPFKFTIPESLDRIKEEFQFLQAQYHSLKLECEKLASEKTEMQRH
  YVMYYEMSYGLNIEMHKQTEIAKRLNTICAQVIPFLSQEHQQQVAQAVERAKQVTMAELN
  AIIGQQQLQAQHLSHGHGPPVPLTPHPSGLQPPGIPPLGGSAGLLALSSALSGQSHLAIK
  DDKKHHDAEHHRDREPGTSNSLLVPDSLRGTDKRRNGPEFSNDIKKRKVDDKDSSHYDSD
  GDKSDDNLVVDVSNEDPSSPRASPAHSPRENGIDKNRLLKKDASSSPASTASSASSTSLK
  SKEMSLHEKASTPVLKSSTPTPRSDMPTPGTSATPGLRPGLGKPPAIDPLVNQAAAGLRT
  PLAVPGPYPAPFGMVPHAGMNGELTSPGAAYASLHNMSPQMSAAAAAAAVVAYGRSPMVG
  FDPPPHMRVPTIPPNLAGIPGGKPAYSFHVTADGQMQPVPFPPDALIGPGIPRHARQINT
  LNHGEVVCAVTISNPTRHVYTGGKGCVKVWDISHPGNKSPVSQLDCLNRDNYIRSCKLLP
  DGCTLIVGGEASTLSIWDLAAPTPRIKAELTSSAPACYALAISPDSKVCFSCCSDGNIAV
  WDLHNQTLVRQFQGHTDGASCIDISNDGTKLWTGGLDNTVRSWDLREGRQLQQHDFTSQI
  FSLGYCPTGEWLAVGMESSNVEVLHVNKPDKYQLHLHESCVLSLKFAYCGKWFVSTGKDN
  LLNAWRTPYGASIFQSKESSSVLSCDISVDDKYIVTGSGDKKATVYEVIY
• Function: Transcriptional corepressor that binds to a number of transcription factors. Inhibits NF-kappa-B-regulated gene expression. Inhibits the transcriptional activation mediated by FOXA2, and by CTNNB1 and TCF family members in Wnt signaling. Enhances FOXG1/BF-1- and HES1-mediated transcriptional repression. The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Unusual function as coactivator for ESRRG.
• Tissue Specificity: In all tissues examined, mostly in brain, liver and muscle.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Notch sig.ling pathway (hsa04330)
• Reactome Pathway:
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Repression of WNT target genes (R-HSA-4641265)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Definitive	Posttranslational Modification	[1]
Carcinoma	DISH9F1N	Definitive	Altered Expression	[2]
Crohn disease	DIS2C5Q8	Definitive	Genetic Variation	[3]
leukaemia	DISS7D1V	Definitive	Biomarker	[1]
Leukemia	DISNAKFL	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[4]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[5]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Depression	DIS3XJ69	Strong	Biomarker	[9]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[10]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[13]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Altered Expression	[14]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[15]
Melanoma	DIS1RRCY	Strong	Altered Expression	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[16]
Psoriasis	DIS59VMN	Strong	Biomarker	[17]
Sarcoma	DISZDG3U	Strong	Altered Expression	[15]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[18]
Soft tissue neoplasm	DISP2OHE	Strong	Biomarker	[19]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[2]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[4]
Adult lymphoma	DISK8IZR	moderate	Biomarker	[1]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[20]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[20]
Lung carcinoma	DISTR26C	moderate	Biomarker	[21]
Lymphoma	DISN6V4S	moderate	Biomarker	[1]
Pancreatic cancer	DISJC981	moderate	Biomarker	[22]
Pediatric lymphoma	DIS51BK2	moderate	Biomarker	[1]
Gastric cancer	DISXGOUK	Disputed	Biomarker	[23]
Mesothelioma	DISKWK9M	Disputed	Biomarker	[24]
Stomach cancer	DISKIJSX	Disputed	Biomarker	[23]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[25]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[26]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[25]
Movement disorder	DISOJJ2D	Limited	Autosomal recessive	[27]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[28]
Type-1/2 diabetes	DISIUHAP	Limited	Posttranslational Modification	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Transducin-like enhancer protein 1 (TLE1) affects the response to substance of Methotrexate.	[44]

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 Transducin-like enhancer protein 1 (TLE1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transducin-like enhancer protein 1 (TLE1).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transducin-like enhancer protein 1 (TLE1).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[35]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[37]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transducin-like enhancer protein 1 (TLE1).	[38]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transducin-like enhancer protein 1 (TLE1).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transducin-like enhancer protein 1 (TLE1).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transducin-like enhancer protein 1 (TLE1).	[39]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Transducin-like enhancer protein 1 (TLE1).	[43]

References

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• [23] Lnc-GIHCG promotes cell proliferation and migration in gastric cancer through miR- 1281 adsorption.Mol Genet Genomic Med. 2019 Jun;7(6):e711. doi: 10.1002/mgg3.711. Epub 2019 May 2.
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• [27] 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.
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• [30] 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.
• [31] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [32] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [33] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [34] 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.
• [35] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [36] 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.
• [37] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
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• [39] 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.
• [40] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [41] 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.
• [42] 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.
• [43] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [44] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.