Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZE3P7)

• DTT Name: TGF-beta receptor type II (TGFBR2)
• Synonyms: Transforminggrowth factor-beta receptor type II; Transforming growth factor-beta receptor type II; TbetaR-II; TGFR-2; TGF-beta type II receptor; TGF-beta receptor type-2
• Gene Name: TGFBR2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: TGFR2_HUMAN
• TTD ID: T49989
• EC Number: EC 2.7.11.30
• Sequence:
  MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFST
  CDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPK
  CIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAI
  SVIIIFYCYRVNRQQKLSSTWETGKTRKLMEFSEHCAIILEDDRSDISSTCANNINHNTE
  LLPIELDTLVGKGRFAEVYKAKLKQNTSEQFETVAVKIFPYEEYASWKTEKDIFSDINLK
  HENILQFLTAEERKTELGKQYWLITAFHAKGNLQEYLTRHVISWEDLRKLGSSLARGIAH
  LHSDHTPCGRPKMPIVHRDLKSSNILVKNDLTCCLCDFGLSLRLDPTLSVDDLANSGQVG
  TARYMAPEVLESRMNLENVESFKQTDVYSMALVLWEMTSRCNAVGEVKDYEPPFGSKVRE
  HPCVESMKDNVLRDRGRPEIPSFWLNHQGIQMVCETLTECWDHDPEARLTAQCVAERFSE
  LEHLDRLSGRSCSEEKIPEDGSLNTTK
• Function: Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating 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 the activation of TGFRB1 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. 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.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  FoxO signaling pathway (hsa04068)
  Endocytosis (hsa04144)
  TGF-beta signaling pathway (hsa04350)
  Osteoclast differentiation (hsa04380)
  Hippo signaling pathway (hsa04390)
  Adherens junction (hsa04520)
  Chagas disease (American trypanosomiasis) (hsa05142)
  HTLV-I infection (hsa05166)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Chronic myeloid leukemia (hsa05220)
• Reactome Pathway:
  TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791)
  SMAD2/3 Phosphorylation Motif Mutants in Cancer (R-HSA-3304356)
  SMAD2/3 MH2 Domain Mutants in Cancer (R-HSA-3315487)
  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)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TGF-BR2 mab	DMWBQ2Z	Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY2109761	DMAWTG3	Discovery agent	N.A.	Investigative	[2]
PMID16539403C15b	DMU2X59	Discovery agent	N.A.	Investigative	[3]
PMID23639540C13a	DMLXOAQ	Discovery agent	N.A.	Investigative	[4]
PMID23639540C13d	DMSTQGH	Discovery agent	N.A.	Investigative	[4]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1795).
• [2] LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 2008 Apr;7(4):829-40.
• [3] Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity vers... J Med Chem. 2006 Mar 23;49(6):2138-42.
• [4] Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3248-52.