Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3P7GZP)

• DOT Name: TGF-beta receptor type-2 (TGFBR2)
• Synonyms: TGFR-2; EC 2.7.11.30; TGF-beta type II receptor; Transforming growth factor-beta receptor type II; TGF-beta receptor type II; TbetaR-II
• Gene Name: TGFBR2
• Related Disease:
  Familial thoracic aortic aneurysm and aortic dissection
  Loeys-Dietz syndrome 2
  Rienhoff syndrome
  Loeys-Dietz syndrome
• UniProt ID: TGFR2_HUMAN
• PDB ID: 1KTZ; 1M9Z; 1PLO; 2PJY; 3KFD; 4P7U; 4XJJ; 5E8V; 5E8Y; 5E91; 5E92; 5QIN; 5TX4; 5TY4; 7DV6
• EC Number: 2.7.11.30
• Pfam ID: PF08917 ; PF07714
• Sequence:
  MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFST
  CDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPK
  CIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAI
  SVIIIFYCYRVNRQQKLSSTWETGKTRKLMEFSEHCAIILEDDRSDISSTCANNINHNTE
  LLPIELDTLVGKGRFAEVYKAKLKQNTSEQFETVAVKIFPYEEYASWKTEKDIFSDINLK
  HENILQFLTAEERKTELGKQYWLITAFHAKGNLQEYLTRHVISWEDLRKLGSSLARGIAH
  LHSDHTPCGRPKMPIVHRDLKSSNILVKNDLTCCLCDFGLSLRLDPTLSVDDLANSGQVG
  TARYMAPEVLESRMNLENVESFKQTDVYSMALVLWEMTSRCNAVGEVKDYEPPFGSKVRE
  HPCVESMKDNVLRDRGRPEIPSFWLNHQGIQMVCETLTECWDHDPEARLTAQCVAERFSE
  LEHLDRLSGRSCSEEKIPEDGSLNTTK
• Function: Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and thus regulates a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways; [Isoform 1]: Has transforming growth factor beta-activated receptor activity; [Isoform 2]: Has transforming growth factor beta-activated receptor activity; [Isoform 3]: Binds TGFB1, TGFB2 and TGFB3 in the picomolar affinity range without the participation of additional receptors. Blocks activation of SMAD2 and SMAD3 by TGFB1.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  FoxO sig.ling pathway (hsa04068)
  Endocytosis (hsa04144)
  Cellular senescence (hsa04218)
  TGF-beta sig.ling pathway (hsa04350)
  Osteoclast differentiation (hsa04380)
  Hippo sig.ling pathway (hsa04390)
  Adherens junction (hsa04520)
  Th17 cell differentiation (hsa04659)
  Relaxin sig.ling pathway (hsa04926)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Chagas disease (hsa05142)
  Hepatitis B (hsa05161)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Chronic myeloid leukemia (hsa05220)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791)
  SMAD2/3 Phosphorylation Motif Mutants in Cancer (R-HSA-3304356)
  TGFBR2 MSI Frameshift Mutants in Cancer (R-HSA-3642279)
  TGFBR2 Kinase Domain Mutants in Cancer (R-HSA-3645790)
  TGFBR1 KD Mutants in Cancer (R-HSA-3656532)
  TGFBR1 LBD Mutants in Cancer (R-HSA-3656535)
  UCH proteinases (R-HSA-5689603)
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Definitive	Autosomal dominant	[1]
Loeys-Dietz syndrome 2	DIS9P1QL	Definitive	Autosomal dominant	[1]
Rienhoff syndrome	DISWC4XA	Definitive	Autosomal dominant	[2]
Loeys-Dietz syndrome	DIS4FUPZ	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bevacizumab	DMSD1UN	Approved	TGF-beta receptor type-2 (TGFBR2) increases the Hypertension ADR of Bevacizumab.	[41]

37 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 TGF-beta receptor type-2 (TGFBR2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of TGF-beta receptor type-2 (TGFBR2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of TGF-beta receptor type-2 (TGFBR2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of TGF-beta receptor type-2 (TGFBR2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of TGF-beta receptor type-2 (TGFBR2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of TGF-beta receptor type-2 (TGFBR2).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of TGF-beta receptor type-2 (TGFBR2).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of TGF-beta receptor type-2 (TGFBR2).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of TGF-beta receptor type-2 (TGFBR2).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of TGF-beta receptor type-2 (TGFBR2).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of TGF-beta receptor type-2 (TGFBR2).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of TGF-beta receptor type-2 (TGFBR2).	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of TGF-beta receptor type-2 (TGFBR2).	[18]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[19]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of TGF-beta receptor type-2 (TGFBR2).	[20]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of TGF-beta receptor type-2 (TGFBR2).	[21]
Ketamine	DMT5HA4	Approved	Ketamine increases the expression of TGF-beta receptor type-2 (TGFBR2).	[22]
Diazepam	DM08E9O	Approved	Diazepam increases the expression of TGF-beta receptor type-2 (TGFBR2).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of TGF-beta receptor type-2 (TGFBR2).	[24]
Glycyrrhizin	DM8M2N3	Phase 3	Glycyrrhizin decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[25]
GEA-6414	DM8J0MK	Phase 1/2	GEA-6414 decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[28]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of TGF-beta receptor type-2 (TGFBR2).	[30]
Acteoside	DM0YHKB	Terminated	Acteoside decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TGF-beta receptor type-2 (TGFBR2).	[32]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[33]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[34]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[35]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of TGF-beta receptor type-2 (TGFBR2).	[36]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[37]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of TGF-beta receptor type-2 (TGFBR2).	[38]
Galangin	DM5TQ2O	Investigative	Galangin increases the expression of TGF-beta receptor type-2 (TGFBR2).	[39]
GW-788388	DMIBUW5	Investigative	GW-788388 decreases the expression of TGF-beta receptor type-2 (TGFBR2).	[40]

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 TGF-beta receptor type-2 (TGFBR2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of TGF-beta receptor type-2 (TGFBR2).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of TGF-beta receptor type-2 (TGFBR2).	[29]

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