Target General Infomation
Target ID
T53389
Former ID
TTDR00998
Target Name
TGF-beta receptor type I
Gene Name
TGFBR1
Synonyms
ALK-5; Activin receptor-like kinase 5; SKR4; Serine/threonine-protein kinase receptor R4; TGF-beta type I receptor; TGFR-1; TbetaRI; Type I TGFbeta receptor kinase; TGFBR1
Target Type
Clinical Trial
Disease Arteriosclerosis [ICD9: 440; ICD10: I70]
Cachexia [ICD9: 799.4; ICD10: R64]
Chronic myelogenous leukaemia [ICD9: 205.1; ICD10: C92.1]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Diabetic nephropathy [ICD9: 250.4; ICD10: E11.21]
Fibrosis [ICD9: 709.2; ICD10: L90.5]
Pulmonary disease [ICD9: 460-519; ICD10: J00-J99]
Pulmonary fibrosis [ICD9: 515, 516.3; ICD10: J84.1]
Scar tissue [ICD10: L00-L99]
Scleroderma [ICD9: 701.0710.1; ICD10: L94.0-L94.1, M34]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, 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 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 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. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylationand activation.
BioChemical Class
Kinase
Target Validation
T53389
UniProt ID
EC Number
EC 2.7.11.30
Sequence
MEAAVAAPRPRLLLLVLAAAAAAAAALLPGATALQCFCHLCTKDNFTCVTDGLCFVSVTE
TTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQDHCNKIELPTTVKSSPG
LGPVELAAVIAGPVCFVCISLMLMVYICHNRTVIHHRVPNEEDPSLDRPFISEGTTLKDL
IYDMTTSGSGSGLPLLVQRTIARTIVLQESIGKGRFGEVWRGKWRGEEVAVKIFSSREER
SWFREAEIYQTVMLRHENILGFIAADNKDNGTWTQLWLVSDYHEHGSLFDYLNRYTVTVE
GMIKLALSTASGLAHLHMEIVGTQGKPAIAHRDLKSKNILVKKNGTCCIADLGLAVRHDS
ATDTIDIAPNHRVGTKRYMAPEVLDDSINMKHFESFKRADIYAMGLVFWEIARRCSIGGI
HEDYQLPYYDLVPSDPSVEEMRKVVCEQKLRPNIPNRWQSCEALRVMAKIMRECWYANGA
ARLTALRIKKTLSQLSQQEGIKM
Drugs and Mode of Action
Drug(s) LY2157299 Drug Info Phase 2/3 Arteriosclerosis [524562], [542748]
LY-2382770 Drug Info Phase 2 Diabetic nephropathy [523022]
Metelimumab Drug Info Phase 1/2 Scleroderma [521527]
P-2745 Drug Info Phase 1 Chronic myelogenous leukaemia [549437]
TEW-7197 Drug Info Phase 1 Solid tumours [524794]
LF-984 Drug Info Terminated Fibrosis [547088]
SM-16 Drug Info Terminated Fibrosis [548543]
Inhibitor 2-phenyl-N-(pyridin-4-yl)quinazolin-4-amine Drug Info [530015]
4-(3-Pyridin-2-Yl-1h-Pyrazol-4-Yl)Quinoline Drug Info [551374]
4-Pyridin-2-yl-5-quinolin-2-yl-thiazol-2-ylamine Drug Info [527174]
4-Pyridin-2-yl-5-quinolin-4-yl-thiazol-2-ylamine Drug Info [527174]
4-Pyridin-3-yl-5-quinolin-4-yl-thiazol-2-ylamine Drug Info [527174]
5''-Quinolin-4-yl-[2,4'']bithiazolyl-2''-ylamine Drug Info [527174]
ACE-435 Drug Info [543481]
Activin-like kinase 5 inhibitor Drug Info [543481]
compound 13d Drug Info [532338]
compound 13r Drug Info [532338]
compound 15b Drug Info [528084]
Compound 67 Drug Info [551374]
DRP-049 Drug Info [543481]
GW-788388 Drug Info [528108]
HTS-466284 Drug Info [528084]
IN-1130 Drug Info [530924]
IN-1166 Drug Info [528880]
LDN-214117 Drug Info [532914]
LF-984 Drug Info [551908]
LY2109761 Drug Info [529427]
SB-431542 Drug Info [530518]
SB-505124 Drug Info [551243]
SB-525334 Drug Info [551243]
SD-208 Drug Info [528660]
SM-16 Drug Info [528553]
TGF-beta receptor 1 kinase inhibitor Drug Info [543481]
TGF-beta receptor 1 kinase inhibitors Drug Info [543481]
Modulator LY2157299 Drug Info [533064]
P-2745 Drug Info [549760]
PTL-101 Drug Info [543481]
TEW-7197 Drug Info [1572591]
WilVent Drug Info [543481]
Antagonist PEG-TGF peptantagonist Drug Info [543481]
TGF-beta Shield Drug Info [543481]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway MAPK signaling pathway
Cytokine-cytokine receptor interaction
FoxO signaling pathway
Endocytosis
TGF-beta signaling pathway
Osteoclast differentiation
Hippo signaling pathway
Adherens junction
Chagas disease (American trypanosomiasis)
Hepatitis B
HTLV-I infection
Pathways in cancer
Colorectal cancer
Pancreatic cancer
Chronic myeloid leukemia
PANTHER Pathway TGF-beta signaling pathway
Pathway Interaction Database Glypican 1 network
ALK1 signaling events
Beta5 beta6 beta7 and beta8 integrin cell surface interactions
TGF-beta receptor signaling
Reactome TGF-beta receptor signaling activates SMADs
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)
SMAD2/3 Phosphorylation Motif Mutants in Cancer
SMAD2/3 MH2 Domain Mutants in Cancer
TGFBR2 Kinase Domain Mutants in Cancer
TGFBR1 KD Mutants in Cancer
TGFBR1 LBD Mutants in Cancer
WikiPathways TGF Beta Signaling Pathway
p38 MAPK Signaling Pathway
MAPK Signaling Pathway
TGF beta Signaling Pathway
Extracellular vesicle-mediated signaling in recipient cells
Cardiac Hypertrophic Response
Signaling by TGF-beta Receptor Complex
Integrated Pancreatic Cancer Pathway
Integrated Breast Cancer Pathway
References
Ref 521527ClinicalTrials.gov (NCT00043706) Safety, Tolerability, and Pharmacokinetics of CAT-192 (Human Anti-TGF-Beta1 Monoclonal Antibody) in Patients With Early Stage Diffuse Systemic Sclerosis. U.S. National Institutes of Health.
Ref 523022ClinicalTrials.gov (NCT01113801) A Study in Patients With Diabetic Kidney Disease. U.S. National Institutes of Health.
Ref 524562ClinicalTrials.gov (NCT02008318) A Study of LY2157299 in Participants With Myelodysplastic Syndromes. U.S. National Institutes of Health.
Ref 524794ClinicalTrials.gov (NCT02160106) First in Human Dose Escalation Study of TEW-7197 in Subjects With Advanced Stage Solid Tumors. U.S. National Institutes of Health.
Ref 542748(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. (Ligand id: 7797).
Ref 547088Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012957)
Ref 548543Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026469)
Ref 549437Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800037259)
Ref
Ref 527174J Med Chem. 2004 Aug 26;47(18):4494-506.Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors.
Ref 527316Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov. 2004 Dec;3(12):1011-22.
Ref 528084J Med Chem. 2006 Mar 23;49(6):2138-42.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.
Ref 528108J Med Chem. 2006 Apr 6;49(7):2210-21.Discovery of 4-{4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): a potent, selective, and orally active transforming growth factor-beta type I receptor inhibitor.
Ref 528553TGF-beta type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody. Int Immunol. 2007 Feb;19(2):117-26. Epub 2006 Nov 29.
Ref 528660Evaluation of the anti-hepatitis C virus effect of novel potent, selective, and orally bioavailable JNK and VEGFR kinase inhibitors. Bioorg Med Chem Lett. 2007 Apr 1;17(7):1843-9. Epub 2007 Jan 24.
Ref 528880J Med Chem. 2007 Jun 28;50(13):3143-7. Epub 2007 Jun 7.Synthesis and biological evaluation of 4(5)-(6-alkylpyridin-2-yl)imidazoles as transforming growth factor-beta type 1 receptor kinase inhibitors.
Ref 529427LY2109761, 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.
Ref 530015Bioorg Med Chem Lett. 2009 Apr 15;19(8):2277-81. Epub 2009 Feb 26.Design of novel quinazoline derivatives and related analogues as potent and selective ALK5 inhibitors.
Ref 530518Bioorg Med Chem Lett. 2010 Jan 1;20(1):326-9. Epub 2009 Oct 29.Pyrazolone based TGFbetaR1 kinase inhibitors.
Ref 530924Bioorg Med Chem. 2010 Jun 15;18(12):4459-67. Epub 2010 Apr 28.Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-beta type 1 receptor kinase inhibitors.
Ref 532052Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov. 2012 Oct;11(10):790-811.
Ref 532338Synthesis 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.
Ref 532914Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J Med Chem. 2014 Oct 9;57(19):7900-15.
Ref 533064Cardiac Safety of TGF-beta Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study. Cardiovasc Toxicol. 2015 Oct;15(4):309-23.
Ref 543481(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: 1788).
Ref 549760Novel potent inhibitor of Bcr-Abl mutated imatinib resistant chronic myeloid leukemia cell lines. Cancer Research. 06/2012; 72(8 Supplement):1822-1822.
Ref 551243Synthesis and biological evaluation of 2-pyridyl-substituted pyrazoles and imidazoles as transforming growth factor-beta type 1 receptor kinase inhibitors, Bioorg. Med. Chem. Lett. 20(14):4228-4232 (2010).
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551908US patent application no. 2013,0028,978, Compositions and methods for wound treatment.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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