Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor EB (TFEB)
• Synonyms: Class E basic helix-loop-helix protein 35; bHLHe35
• Gene Name: TFEB
• Related Disease:
  Adult glioblastoma
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Bacterial infection
  Breast cancer
  Breast neoplasm
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Congestive heart failure
  Coronary atherosclerosis
  Epithelial ovarian cancer
  Fatty liver disease
  Gaucher disease
  Glioma
  Glycogen storage disease type II
  Microphthalmia
  Myocardial ischemia
  Neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Vascular disease
  Amyotrophic lateral sclerosis
  Carcinoma
  Glioblastoma multiforme
  Kidney cancer
  Mucolipidosis type IV
  Pulmonary fibrosis
  Renal carcinoma
  Breast carcinoma
  Kidney neoplasm
  Melanoma
  Obesity
• UniProt ID: TFEB_HUMAN
• PDB ID: 7UX2; 7UXC; 7UXH; 7Y62
• Pfam ID: PF11851 ; PF00010 ; PF15951
• Sequence:
  MASRIGLRMQLMREQAQQEEQRERMQQQAVMHYMQQQQQQQQQQLGGPPTPAINTPVHFQ
  SPPPVPGEVLKVQSYLENPTSYHLQQSQHQKVREYLSETYGNKFAAHISPAQGSPKPPPA
  ASPGVRAGHVLSSSAGNSAPNSPMAMLHIGSNPERELDDVIDNIMRLDDVLGYINPEMQM
  PNTLPLSSSHLNVYSSDPQVTASLVGVTSSSCPADLTQKRELTDAESRALAKERQKKDNH
  NLIERRRRFNINDRIKELGMLIPKANDLDVRWNKGTILKASVDYIRRMQKDLQKSRELEN
  HSRRLEMTNKQLWLRIQELEMQARVHGLPTTSPSGMNMAELAQQVVKQELPSEEGPGEAL
  MLGAEVPDPEPLPALPPQAPLPLPTQPPSPFHHLDFSHSLSFGGREDEGPPGYPEPLAPG
  HGSPFPSLSKKDLDLMLLDDSLLPLASDPLLSTMSPEASKASSRRSSFSMEEGDVL
• Function: Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response. Specifically recognizes and binds E-box sequences (5'-CANNTG-3'); efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF. Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFEB phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation. Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity. Specifically recognizes and binds the CLEAR-box sequence (5'-GTCACGTGAC-3') present in the regulatory region of many lysosomal genes, leading to activate their expression, thereby playing a central role in expression of lysosomal genes. Regulates lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1. Acts as a positive regulator of autophagy by promoting expression of genes involved in autophagy. In association with TFE3, activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity. Specifically recognizes the gamma-E3 box, a subset of E-boxes, present in the heavy-chain immunoglobulin enhancer. Plays a role in the signal transduction processes required for normal vascularization of the placenta. Involved in the immune response to infection by the bacteria S.aureus, S.typhimurium or S.enterica: infection promotes itaconate production, leading to alkylation, resulting in nuclear localization and transcription factor activity. Itaconate-mediated alkylation activates TFEB-dependent lysosomal biogenesis, facilitating the bacteria clearance during the antibacterial innate immune response. In association with ACSS2, promotes the expression of genes involved in lysosome biogenesis and both autophagy upon glucose deprivation.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Mitophagy - animal (hsa04137)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Bacterial infection	DIS5QJ9S	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Genetic Variation	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[8]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[8]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[10]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[12]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[13]
Gaucher disease	DISTW5JG	Strong	Genetic Variation	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Glycogen storage disease type II	DISXZPBC	Strong	Altered Expression	[15]
Microphthalmia	DISGEBES	Strong	Biomarker	[16]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[17]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[20]
Prostate cancer	DISF190Y	Strong	Altered Expression	[21]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[22]
Vascular disease	DISVS67S	Strong	Biomarker	[23]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[24]
Carcinoma	DISH9F1N	moderate	Biomarker	[25]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[1]
Kidney cancer	DISBIPKM	moderate	Biomarker	[26]
Mucolipidosis type IV	DISWJY3U	moderate	Biomarker	[27]
Pulmonary fibrosis	DISQKVLA	moderate	Biomarker	[28]
Renal carcinoma	DISER9XT	moderate	Biomarker	[26]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[29]
Kidney neoplasm	DISBNZTN	Limited	Altered Expression	[30]
Melanoma	DIS1RRCY	Limited	Altered Expression	[31]
Obesity	DIS47Y1K	Limited	Biomarker	[32]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Apilimod dimesylate	DM4N2O0	Phase 2	Transcription factor EB (TFEB) increases the response to substance of Apilimod dimesylate.	[50]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	Transcription factor EB (TFEB) affects the response to substance of 4-hydroxy-2-nonenal.	[51]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transcription factor EB (TFEB).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcription factor EB (TFEB).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transcription factor EB (TFEB).	[35]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transcription factor EB (TFEB).	[36]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transcription factor EB (TFEB).	[37]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor EB (TFEB).	[38]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transcription factor EB (TFEB).	[39]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor EB (TFEB).	[42]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transcription factor EB (TFEB).	[37]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Transcription factor EB (TFEB).	[43]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Transcription factor EB (TFEB).	[39]
GDC0941	DM1YAK6	Phase 2	GDC0941 increases the expression of Transcription factor EB (TFEB).	[45]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 increases the expression of Transcription factor EB (TFEB).	[48]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Transcription factor EB (TFEB).	[48]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Transcription factor EB (TFEB).	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Imatinib	DM7RJXL	Approved	Imatinib affects the localization of Transcription factor EB (TFEB).	[40]
Prochlorperazine	DM53SRA	Approved	Prochlorperazine affects the localization of Transcription factor EB (TFEB).	[41]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone affects the localization of Transcription factor EB (TFEB).	[44]
Fluphenazine	DMIT8LX	Investigative	Fluphenazine affects the localization of Transcription factor EB (TFEB).	[41]

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 increases the methylation of Transcription factor EB (TFEB).	[46]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription factor EB (TFEB).	[47]

References

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• [51] Upregulation of the TFEB-mediated lysosome function relieves 4-Hydroxynonenal-Induced apoptosis. Chem Biol Interact. 2022 Aug 1;362:109963. doi: 10.1016/j.cbi.2022.109963. Epub 2022 May 9.