Target Information
Target General Infomation | |||||
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Target ID |
T53389
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Former ID |
TTDR00998
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Target Name |
TGF-beta receptor type I
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Gene Name |
TGFBR1
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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
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Target Type |
Clinical Trial
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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 fibrosis [ICD9: 515, 516.3; ICD10: J84.1] | |||||
Pulmonary disease [ICD9: 460-519; ICD10: J00-J99] | |||||
Scleroderma [ICD9: 701.0710.1; ICD10: L94.0-L94.1, M34] | |||||
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
Scar tissue [ICD10: L00-L99] | |||||
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.
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BioChemical Class |
Kinase
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Target Validation |
T53389
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UniProt ID | |||||
EC Number |
EC 2.7.11.30
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Sequence |
MEAAVAAPRPRLLLLVLAAAAAAAAALLPGATALQCFCHLCTKDNFTCVTDGLCFVSVTE
TTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQDHCNKIELPTTVKSSPG LGPVELAAVIAGPVCFVCISLMLMVYICHNRTVIHHRVPNEEDPSLDRPFISEGTTLKDL IYDMTTSGSGSGLPLLVQRTIARTIVLQESIGKGRFGEVWRGKWRGEEVAVKIFSSREER SWFREAEIYQTVMLRHENILGFIAADNKDNGTWTQLWLVSDYHEHGSLFDYLNRYTVTVE GMIKLALSTASGLAHLHMEIVGTQGKPAIAHRDLKSKNILVKKNGTCCIADLGLAVRHDS ATDTIDIAPNHRVGTKRYMAPEVLDDSINMKHFESFKRADIYAMGLVFWEIARRCSIGGI HEDYQLPYYDLVPSDPSVEEMRKVVCEQKLRPNIPNRWQSCEALRVMAKIMRECWYANGA ARLTALRIKKTLSQLSQQEGIKM |
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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 521527 | ClinicalTrials.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 523022 | ClinicalTrials.gov (NCT01113801) A Study in Patients With Diabetic Kidney Disease. U.S. National Institutes of Health. | ||||
Ref 524562 | ClinicalTrials.gov (NCT02008318) A Study of LY2157299 in Participants With Myelodysplastic Syndromes. U.S. National Institutes of Health. | ||||
Ref 524794 | ClinicalTrials.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 547088 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012957) | ||||
Ref 527174 | J 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 527316 | Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov. 2004 Dec;3(12):1011-22. | ||||
Ref 528084 | J 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 528108 | J 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 528553 | TGF-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 528660 | Evaluation 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 528880 | J 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 529427 | 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. | ||||
Ref 530015 | Bioorg 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 530518 | Bioorg Med Chem Lett. 2010 Jan 1;20(1):326-9. Epub 2009 Oct 29.Pyrazolone based TGFbetaR1 kinase inhibitors. | ||||
Ref 530924 | Bioorg 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 532052 | Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov. 2012 Oct;11(10):790-811. | ||||
Ref 532338 | 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. | ||||
Ref 532914 | Structure-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 533064 | Cardiac 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 549760 | Novel potent inhibitor of Bcr-Abl mutated imatinib resistant chronic myeloid leukemia cell lines. Cancer Research. 06/2012; 72(8 Supplement):1822-1822. | ||||
Ref 551243 | Synthesis 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). |
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