transforming growth factor beta receptor 1

Target id: 1788

Nomenclature: transforming growth factor beta receptor 1

Abbreviated Name: TGFBR1

Family: Type I receptor serine/threonine kinases

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for transforming growth factor beta receptor 1 in GtoImmuPdb

Quaternary Structure: Complexes
Transforming growth factor β receptor
Growth/differentiation factor receptors
Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 426 9q22 TGFBR1 transforming growth factor beta receptor 1
Mouse 1 503 4 Tgfbr1 transforming growth factor, beta receptor I
Rat 1 497 5q22 Tgfbr1 transforming growth factor, beta receptor 1
Previous and Unofficial Names
serine/threonine-protein kinase receptor R4 | SKR4 | TGFβ receptor I | TGFR-1 | activin A receptor type II-like kinase, 53kDa | TbetaRI | ALK5 | ACVRLK4 | transforming growth factor, beta receptor 1 | transforming growth factor
Database Links
BRENDA
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of TGF-beta receptor I kinase with inhibitor
PDB Id:  1PY5
Resolution:  2.3Å
Species:  Human
References:  16
Image of receptor 3D structure from RCSB PDB
Description:  TGF-beta receptor type 1 in complex with SB-431542.
PDB Id:  3TZM
Ligand:  SB-431542
Resolution:  1.7Å
Species:  Human
References:  14
Enzyme Reaction
EC Number: 2.7.11.30
Natural/Endogenous Ligands
growth/differentiation factor-11 {Sp: Human}

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
LY2109761 Hs Inhibition 7.4 pKi 12
pKi 7.4 (Ki 3.8x10-8 M) [12]
vactosertib Hs Inhibition 8.0 pIC50 8
pIC50 8.0 (IC50 1.1x10-8 M) [8]
Description: Measured using Reaction Biology Corporation's HotSpot kinase assay.
TGF-beta RI kinase inhibitor Hs Inhibition 7.6 pIC50 3
pIC50 7.6 (IC50 2.7x10-8 M) [3]
SD-208 Hs Inhibition 7.3 pIC50 15
pIC50 7.3 (IC50 5.3x10-8 M) [15]
TGF-beta RI inhibitor III Hs Inhibition 7.3 pIC50 9
pIC50 7.3 (IC50 5.4x10-8 M) [9]
Description: Assay used purified human TGFβR1 kinase domain produced in Sf9 insect cells.
galunisertib Hs Inhibition 7.3 pIC50
pIC50 7.3 (IC50 5.6x10-8 M)
Description: Inhibition of a 6×-HIS tagged cytoplasmic kinase domain representing TGFβR1
compound 13r [PMID: 23639540] Hs Inhibition 7.1 pIC50 6
pIC50 7.1 (IC50 7.5x10-8 M) [6]
compound 15b [PMID: 16539403] Hs Inhibition 7.1 pIC50 11
pIC50 7.1 (IC50 7.9x10-8 M) [11]
SB-431542 Hs Inhibition 7.0 pIC50 4
pIC50 7.0 (IC50 9.4x10-8 M) [4]
Description: Inhibition of TGFBR1-induced Smad3 phosphorylation in vitro.
compound 13d [PMID: 23639540] Hs Inhibition 6.8 pIC50 6
pIC50 6.8 (IC50 1.78x10-7 M) [6]
BIX02189 Hs Inhibition 6.2 pIC50 17
pIC50 6.2 (IC50 5.8x10-7 M) [17]
LDN-214117 Hs Inhibition 5.5 pIC50 13
pIC50 5.5 (IC50 3x10-6 M) [13]
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
H. polygyrus TGF-β mimic Hs Agonist 6.5 pKd 10
pKd 6.5 (Kd 3.5x10-7 M) [10]
Description: Measured using a SPR assay and immobilised ligand.
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 5,18

Key to terms and symbols Click column headers to sort
Target used in screen: TGFBR1
Ligand Sp. Type Action Affinity Units
PP-242 Hs Inhibitor Inhibition 7.0 pKd
lestaurtinib Hs Inhibitor Inhibition 6.9 pKd
NVP-TAE684 Hs Inhibitor Inhibition 6.7 pKd
dasatinib Hs Inhibitor Inhibition 6.6 pKd
crizotinib Hs Inhibitor Inhibition 6.0 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.0 pKd
PD-173955 Hs Inhibitor Inhibition 5.8 pKd
cediranib Hs Inhibitor Inhibition 5.8 pKd
staurosporine Hs Inhibitor Inhibition 5.7 pKd
tamatinib Hs Inhibitor Inhibition 5.6 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 2,7

Key to terms and symbols Click column headers to sort
Target used in screen: TGFBR1/ALK5(TGFBR1)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
TGF-beta RI inhibitor III Hs Inhibitor Inhibition 35.8 10.0 0.0
TGF-beta RI kinase inhibitor Hs Inhibitor Inhibition 41.6 6.0 0.0
dasatinib Hs Inhibitor Inhibition 76.7
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 81.8 13.0 2.0
casein kinase II inhibitor III Hs Inhibitor Inhibition 90.8 101.0 97.0
JAK3 inhibitor IV Hs Inhibitor Inhibition 92.5 76.0 74.0
ATM/ATR kinase inhibitor Hs Inhibitor Inhibition 92.6 98.0 87.0
AG 112 Hs Inhibitor Inhibition 93.0 91.0 91.0
p38 MAP kinase inhibitor III Hs Inhibitor Inhibition 93.3 114.0 114.0
Flt-3 inhibitor II Hs Inhibitor Inhibition 93.4 79.0 80.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Aortic aneurysm, familial abdominal, 1; AAA1
Synonyms: Familial abdominal aortic aneurysm [Disease Ontology: DOID:0050306]
Familial thoracic aortic aneurysm and aortic dissection [Orphanet: ORPHA91387]
Disease Ontology: DOID:0050306
OMIM: 100070
Orphanet: ORPHA91387
Disease:  Loeys-Dietz syndrome 1; LDS1
Synonyms: Loeys-Dietz syndrome [Orphanet: ORPHA60030] [Disease Ontology: DOID:0050466]
Disease Ontology: DOID:0050466
OMIM: 609192
Orphanet: ORPHA60030
Disease:  Multiple self-healing squamous epithelioma, susceptibility to; MSSE
Synonyms: Multiple keratoacanthoma, Ferguson-Smith type [Orphanet: ORPHA65748]
OMIM: 132800
Orphanet: ORPHA65748

References

Show »

1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

3. Bamborough P, Drewry D, Harper G, Smith GK, Schneider K. (2008) Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. J. Med. Chem., 51 (24): 7898-914. [PMID:19035792]

4. Callahan JF, Burgess JL, Fornwald JA, Gaster LM, Harling JD, Harrington FP, Heer J, Kwon C, Lehr R, Mathur A et al.. (2002) Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J. Med. Chem., 45 (5): 999-1001. [PMID:11855979]

5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

6. Engers DW, Frist AY, Lindsley CW, Hong CC, Hopkins CR. (2013) 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., 23 (11): 3248-52. [PMID:23639540]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

8. Jin CH, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Lee HJ, Park SJ, Park HJ, Lee K, Sheen YY et al.. (2014) Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. J. Med. Chem., 57 (10): 4213-38. [PMID:24786585]

9. Jin CH, Sreenu D, Krishnaiah M, Subrahmanyam VB, Rao KS, Nagendra Mohan AV, Park CY, Son JY, Son DH, Park HJ et al.. (2011) Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors. Eur J Med Chem, 46 (9): 3917-25. [PMID:21696866]

10. Johnston CJC, Smyth DJ, Kodali RB, White MPJ, Harcus Y, Filbey KJ, Hewitson JP, Hinck CS, Ivens A, Kemter AM et al.. (2017) A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells. Nat Commun, 8 (1): 1741. [PMID:29170498]

11. Li HY, Wang Y, Heap CR, King CH, Mundla SR, Voss M, Clawson DK, Yan L, Campbell RM, Anderson BD et al.. (2006) Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity versus transforming growth factor-beta type II receptor kinase and mixed lineage kinase-7. J. Med. Chem., 49 (6): 2138-42. [PMID:16539403]

12. Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ. (2008) 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., 7 (4): 829-40. [PMID:18413796]

13. Mohedas AH, Wang Y, Sanvitale CE, Canning P, Choi S, Xing X, Bullock AN, Cuny GD, Yu PB. (2014) Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J. Med. Chem., 57 (19): 7900-15. [PMID:25101911]

14. Ogunjimi AA, Zeqiraj E, Ceccarelli DF, Sicheri F, Wrana JL, David L. (2012) Structural basis for specificity of TGFβ family receptor small molecule inhibitors. Cell. Signal., 24 (2): 476-83. [PMID:21983015]

15. Raboisson P, Lenz O, Lin TI, Surleraux D, Chakravarty S, Scholliers A, Vermeiren K, Delouvroy F, Verbinnen T, Simmen K. (2007) Evaluation of the anti-hepatitis C virus effect of novel potent, selective, and orally bioavailable JNK and VEGFR kinase inhibitors. Bioorg. Med. Chem. Lett., 17 (7): 1843-9. [PMID:17289388]

16. Sawyer JS, Beight DW, Britt KS, Anderson BD, Campbell RM, Goodson T, Herron DK, Li HY, McMillen WT, Mort N et al.. (2004) Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg. Med. Chem. Lett., 14 (13): 3581-4. [PMID:15177479]

17. Tatake RJ, O'Neill MM, Kennedy CA, Wayne AL, Jakes S, Wu D, Kugler Jr SZ, Kashem MA, Kaplita P, Snow RJ. (2008) Identification of pharmacological inhibitors of the MEK5/ERK5 pathway. Biochem. Biophys. Res. Commun., 377 (1): 120-5. [PMID:18834865]

18. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Type I receptor serine/threonine kinases: transforming growth factor beta receptor 1. Last modified on 27/11/2017. Accessed on 19/07/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1788.