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transforming growth factor beta receptor 1

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1788

Nomenclature: transforming growth factor beta receptor 1

Abbreviated Name: TGFBR1

Family: Type I receptor serine/threonine kinases

Contents:

Quaternary Structure: Complexes
Transforming growth factor β receptor
Growth/differentiation factor receptors
Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 503 9q22.33 TGFBR1 transforming growth factor beta receptor 1
Mouse 1 503 4 26.02 cM Tgfbr1 transforming growth factor, beta receptor I
Rat 1 501 5q22 Tgfbr1 transforming growth factor, beta receptor 1
Previous and Unofficial Names Click here for help
activin A receptor type II-like kinase, 53kDa | ACVRLK4 | ALK5 | serine/threonine-protein kinase receptor R4 | SKR4 | TbetaRI | TGFβ receptor I | TGFR-1 | transforming growth factor | transforming growth factor, beta receptor 1
Database Links Click here for help
Alphafold P36897 (Hs), Q64729 (Mm), P80204 (Rn)
BRENDA 2.7.11.30
ChEMBL Target CHEMBL4439 (Hs), CHEMBL2021750 (Mm), CHEMBL4523265 (Rn)
Ensembl Gene ENSG00000106799 (Hs), ENSMUSG00000007613 (Mm), ENSRNOG00000007036 (Rn)
Entrez Gene 7046 (Hs), 21812 (Mm)
Human Protein Atlas ENSG00000106799 (Hs)
KEGG Enzyme 2.7.11.30
KEGG Gene hsa:7046 (Hs), mmu:21812 (Mm)
OMIM 190181 (Hs)
Orphanet ORPHA120065 (Hs)
Pharos P36897 (Hs)
RefSeq Nucleotide NM_001130916 (Hs), NM_009370 (Mm), NM_012775 (Rn)
RefSeq Protein NP_001124388 (Hs), NP_033396 (Mm), NP_036907 (Rn)
SynPHARM 81808 (in complex with SB-431542)
80583 (in complex with TGF-beta RI kinase inhibitor)
UniProtKB P36897 (Hs), Q64729 (Mm), P80204 (Rn)
Wikipedia TGFBR1 (Hs)
Selected 3D Structures Click here for help
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:  17
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:  15
Enzyme Reaction Click here for help
EC Number: 2.7.11.30
Natural/Endogenous Ligands Click here for help
growth/differentiation factor-11 {Sp: Human}

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LY2109761 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.4 pKi 13
⤷ pKi 7.4 (Ki 3.8x10-8 M) [13]
BMS-986260 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.8 pIC50 19
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [19]
vactosertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 9
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [9]
Description: Measured using Reaction Biology Corporation's HotSpot kinase assay.
TGF-beta RI kinase inhibitor Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.6 pIC50 4
⤷ pIC50 7.6 (IC50 2.7x10-8 M) [4]
SD-208 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 16
⤷ pIC50 7.3 (IC50 5.3x10-8 M) [16]
TGF-beta RI inhibitor III Small molecule or natural product Primary target of this compound Hs Inhibition 7.3 pIC50 10
⤷ pIC50 7.3 (IC50 5.4x10-8 M) [10]
Description: Assay used purified human TGFβR1 kinase domain produced in Sf9 insect cells.
compound 13r [PMID: 23639540] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 7
⤷ pIC50 7.1 (IC50 7.5x10-8 M) [7]
compound 15b [PMID: 16539403] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.1 pIC50 12
⤷ pIC50 7.1 (IC50 7.9x10-8 M) [12]
SB-431542 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.0 pIC50 5
⤷ pIC50 7.0 (IC50 9.4x10-8 M) [5]
Description: Inhibition of TGFBR1-induced Smad3 phosphorylation in vitro.
galunisertib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 6.8 – 7.3 pIC50 21
⤷ pIC50 7.3 (IC50 5.6x10-8 M)
Description: Inhibition of a 6×-HIS tagged cytoplasmic kinase domain representing TGFβR1
pIC50 6.8 (IC50 1.72x10-7 M) [21]
Description: Result from a DiscoverX KINOMEscan platform kinase activity assay.
compound 13d [PMID: 23639540] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.8 pIC50 7
⤷ pIC50 6.8 (IC50 1.78x10-7 M) [7]
BIX02189 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 18
⤷ pIC50 6.2 (IC50 5.8x10-7 M) [18]
LDN-214117 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.5 pIC50 14
⤷ pIC50 5.5 (IC50 3x10-6 M) [14]
zilurgisertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.2 pIC50 3
⤷ pIC50 5.2 (IC50 6.28x10-6 M) [3]
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
H. polygyrus TGF-β mimic Peptide Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 6.5 pKd 11
⤷ pKd 6.5 (Kd 3.5x10-7 M) [11]
Description: Measured using a SPR assay and immobilised ligand.
DiscoveRx KINOMEscan® screen Click here for help
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: 6,20
Key to terms and symbols Click column headers to sort
Target used in screen: TGFBR1
Ligand Sp. Type Action Value Parameter
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.9 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.6 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.0 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.0 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.8 pKd
cediranib Small molecule or natural product Hs Inhibitor Inhibition 5.8 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.7 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand 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 Click here for help
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: 2,8
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 Small molecule or natural product Hs Inhibitor Inhibition 35.8 10.0 0.0
TGF-beta RI kinase inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 41.6 6.0 0.0
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 76.7
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 81.8 13.0 2.0
casein kinase II inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 90.8 101.0 97.0
JAK3 inhibitor IV Small molecule or natural product Hs Inhibitor Inhibition 92.5 76.0 74.0
ATM/ATR kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 92.6 98.0 87.0
AG 112 Small molecule or natural product Hs Inhibitor Inhibition 93.0 91.0 91.0
p38 MAP kinase inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 93.3 114.0 114.0
Flt-3 inhibitor II Small molecule or natural product Hs Inhibitor Inhibition 93.4 79.0 80.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
The role of TGFBR1 in immuno-oncology is reviewed in [1].
Immuno Process Associations
Immuno Process:  Immune system development
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
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. Arista L, Babu S, Bian J, Cui K, Dillon MP, Lattmann R, Li J, Liao L, Lizos D, Ramos R et al.. (2021) Aminopyridine derivatives and their use as selective alk-2 inhibitors. Patent number: US20210155606A1. Assignee: Novartis AG. Priority date: 20/07/2016. Publication date: 27/05/2021.

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. Velaparthi U, Darne CP, Warrier J, Liu P, Rahaman H, Augustine-Rauch K, Parrish K, Yang Z, Swanson J, Brown J et al.. (2020) Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent. ACS Med Chem Lett, 11 (2): 172-178. DOI: 10.1021/acsmedchemlett.9b00552 [PMID:32071685]

20. 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]

21. Yingling JM, McMillen WT, Yan L, Huang H, Sawyer JS, Graff J, Clawson DK, Britt KS, Anderson BD, Beight DW et al.. (2018) Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor. Oncotarget, 9 (6): 6659-6677. [PMID:29467918]

How to cite this page

Type I receptor serine/threonine kinases: transforming growth factor beta receptor 1. Last modified on 04/02/2022. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1788.