Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWS5I5H)

• DOT Name: Lymphoid enhancer-binding factor 1 (LEF1)
• Synonyms: LEF-1; T cell-specific transcription factor 1-alpha; TCF1-alpha
• Gene Name: LEF1
• Related Disease:
  Acute myelogenous leukaemia
  Adult glioblastoma
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Burkitt lymphoma
  Carcinoma
  Childhood acute lymphoblastic leukemia
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Familial adenomatous polyposis
  Gastric cancer
  Hepatocellular carcinoma
  Leukemia
  Lung cancer
  Mantle cell lymphoma
  Myelodysplastic syndrome
  Neoplasm
  Neuroblastoma
  Osteoarthritis
  Severe congenital neutropenia
  Small lymphocytic lymphoma
  Stomach cancer
  X-linked hypohidrotic ectodermal dysplasia
  Cleft palate
  Glioblastoma multiforme
  Isolated cleft palate
  leukaemia
  Metastatic malignant neoplasm
  Nasopharyngeal carcinoma
  Primary myelofibrosis
  Melanoma
  Prostate cancer
  Prostate carcinoma
  Acute lymphocytic leukaemia
  Autoimmune disease
  Bone osteosarcoma
  Colon cancer
  Endometrial cancer
  Endometrial carcinoma
  Lymphoid leukemia
  Osteosarcoma
• UniProt ID: LEF1_HUMAN
• Pfam ID: PF08347 ; PF00505
• Sequence:
  MPQLSGGGGGGGGDPELCATDEMIPFKDEGDPQKEKIFAEISHPEEEGDLADIKSSLVNE
  SEIIPASNGHEVARQAQTSQEPYHDKAREHPDDGKHPDGGLYNKGPSYSSYSGYIMMPNM
  NNDPYMSNGSLSPPIPRTSNKVPVVQPSHAVHPLTPLITYSDEHFSPGSHPSHIPSDVNS
  KQGMSRHPPAPDIPTFYPLSPGGVGQITPPLGWQGQPVYPITGGFRQPYPSSLSVDTSMS
  RFSHHMIPGPPGPHTTGIPHPAIVTPQVKQEHPHTDSDLMHVKPQHEQRKEQEPKRPHIK
  KPLNAFMLYMKEMRANVVAECTLKESAAINQILGRRWHALSREEQAKYYELARKERQLHM
  QLYPGWSARDNYGKKKKRKREKLQESASGTGPRMTAAYI
• Function: Transcription factor that binds DNA in a sequence-specific manner. Participates in the Wnt signaling pathway. Activates transcription of target genes in the presence of CTNNB1 and EP300. PIAG antagonizes both Wnt-dependent and Wnt-independent activation by LEF1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by LEF1 and CTNNB1. Regulates T-cell receptor alpha enhancer function. Required for IL17A expressing gamma-delta T-cell maturation and development, via binding to regulator loci of BLK to modulate expression. Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, expression is repressed during the bell stage by MSX1-mediated inhibition of CTNNB1 signaling. May play a role in hair cell differentiation and follicle morphogenesis; [Isoform 1]: Transcriptionally activates MYC and CCND1 expression and enhances proliferation of pancreatic tumor cells; [Isoform 3]: Lacks the CTNNB1 interaction domain and may therefore be an antagonist for Wnt signaling; [Isoform 5]: Transcriptionally activates the fibronectin promoter, binds to and represses transcription from the E-cadherin promoter in a CTNNB1-independent manner, and is involved in reducing cellular aggregation and increasing cell migration of pancreatic cancer cells.
• Tissue Specificity: Detected in thymus. Not detected in normal colon, but highly expressed in colon cancer biopsies and colon cancer cell lines. Expressed in several pancreatic tumors and weakly expressed in normal pancreatic tissue. Isoforms 1 and 5 are detected in several pancreatic cell lines.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)
  Adherens junction (hsa04520)
  Melanogenesis (hsa04916)
  Cushing syndrome (hsa04934)
  Alcoholic liver disease (hsa04936)
  Salmonella infection (hsa05132)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Endometrial cancer (hsa05213)
  Prostate cancer (hsa05215)
  Thyroid cancer (hsa05216)
  Basal cell carcinoma (hsa05217)
  Acute myeloid leukemia (hsa05221)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
• Reactome Pathway:
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Ca2+ pathway (R-HSA-4086398)
  Binding of TCF/LEF (R-HSA-4411364)
  Repression of WNT target genes (R-HSA-4641265)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  RUNX3 regulates WNT signaling (R-HSA-8951430)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  Cardiogenesis (R-HSA-9733709)
  Germ layer formation at gastrulation (R-HSA-9754189)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Formation of axial mesoderm (R-HSA-9796292)
  Somitogenesis (R-HSA-9824272)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[11]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[17]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[18]
Neoplasm	DISZKGEW	Strong	Biomarker	[19]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[20]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[21]
Severe congenital neutropenia	DISES99N	Strong	Altered Expression	[22]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[23]
Stomach cancer	DISKIJSX	Strong	Biomarker	[13]
X-linked hypohidrotic ectodermal dysplasia	DISST0XM	Strong	Altered Expression	[24]
Cleft palate	DIS6G5TF	moderate	Biomarker	[25]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[26]
Isolated cleft palate	DISV80CD	moderate	Biomarker	[25]
leukaemia	DISS7D1V	moderate	Biomarker	[15]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[27]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[28]
Primary myelofibrosis	DIS6L0CN	moderate	Altered Expression	[29]
Melanoma	DIS1RRCY	Disputed	Biomarker	[30]
Prostate cancer	DISF190Y	Disputed	Altered Expression	[31]
Prostate carcinoma	DISMJPLE	Disputed	Altered Expression	[31]
Acute lymphocytic leukaemia	DISPX75S	Limited	Biomarker	[6]
Autoimmune disease	DISORMTM	Limited	Biomarker	[32]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[33]
Colon cancer	DISVC52G	Limited	Biomarker	[8]
Endometrial cancer	DISW0LMR	Limited	Altered Expression	[34]
Endometrial carcinoma	DISXR5CY	Limited	Altered Expression	[34]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[35]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Lymphoid enhancer-binding factor 1 (LEF1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Lymphoid enhancer-binding factor 1 (LEF1).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[37]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[38]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[39]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[40]
Adenosine	DMM2NSK	Approved	Adenosine increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[42]
Ethacrynic acid	DM60QMR	Approved	Ethacrynic acid decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[43]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[44]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[45]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[46]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[48]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[49]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[50]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[51]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[52]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[53]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[54]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[55]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[42]
eucalyptol	DME5CK3	Investigative	eucalyptol decreases the expression of Lymphoid enhancer-binding factor 1 (LEF1).	[56]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Lovastatin	DM9OZWQ	Approved	Lovastatin affects the localization of Lymphoid enhancer-binding factor 1 (LEF1).	[41]

References

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