Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTP4520)

• DTT Name: TGF-beta receptor type I (TGFBR1)
• Synonyms: Type I TGFbeta receptor kinase; Transforming growth factor-beta receptor type I; TbetaRI; TbetaR-I; TGFR-1; TGF-beta type I receptor; TGF-beta receptor type-1; Serine/threonine-protein kinase receptor R4; SKR4; Activin receptor-like kinase 5; Activin A receptor type II-like protein kinase of 53kD; ALK5; ALK-5
• Gene Name: TGFBR1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: TGFR1_HUMAN
• TTD ID: T53389
• EC Number: EC 2.7.11.30
• Sequence:
  MEAAVAAPRPRLLLLVLAAAAAAAAALLPGATALQCFCHLCTKDNFTCVTDGLCFVSVTE
  TTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQDHCNKIELPTTVKSSPG
  LGPVELAAVIAGPVCFVCISLMLMVYICHNRTVIHHRVPNEEDPSLDRPFISEGTTLKDL
  IYDMTTSGSGSGLPLLVQRTIARTIVLQESIGKGRFGEVWRGKWRGEEVAVKIFSSREER
  SWFREAEIYQTVMLRHENILGFIAADNKDNGTWTQLWLVSDYHEHGSLFDYLNRYTVTVE
  GMIKLALSTASGLAHLHMEIVGTQGKPAIAHRDLKSKNILVKKNGTCCIADLGLAVRHDS
  ATDTIDIAPNHRVGTKRYMAPEVLDDSINMKHFESFKRADIYAMGLVFWEIARRCSIGGI
  HEDYQLPYYDLVPSDPSVEEMRKVVCEQKLRPNIPNRWQSCEALRVMAKIMRECWYANGA
  ARLTALRIKKTLSQLSQQEGIKM
• 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 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 phosphorylation and activation. 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.
• 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)
  Hepatitis B (hsa05161)
  HTLV-I infection (hsa05166)
  Pathways in cancer (hsa05200)
  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

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY2157299	DMP8HW1	Arteriosclerosis	BD40	Phase 2/3	[1]
TEW-7197	DM2LBC3	Myeloproliferative neoplasm	2A20	Phase 2	[2]
Metelimumab	DMENFD6	Scleroderma	4A42	Phase 1/2	[3]
LY3200882	DMQP6VB	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
P-2745	DMJ3PNS	Chronic myelogenous leukaemia	2A20.0	Phase 1	[5]
PF-06952229	DMDQJEZ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
TP-0184	DMJVZBC	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SB-431542	DM0YOXQ	Pulmonary fibrosis	CB03.4	Preclinical	[8]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LF-984	DMIYMS2	Fibrosis	GA14-GC01	Terminated	[9]
SM-16	DMHXJV2	Fibrosis	GA14-GC01	Terminated	[10]

22 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-phenyl-N-(pyridin-4-yl)quinazolin-4-amine	DMEFOV6	Discovery agent	N.A.	Investigative	[11]
4-Pyridin-2-yl-5-quinolin-2-yl-thiazol-2-ylamine	DMY8ZLM	Discovery agent	N.A.	Investigative	[12]
4-Pyridin-2-yl-5-quinolin-4-yl-thiazol-2-ylamine	DM6RVB3	Discovery agent	N.A.	Investigative	[12]
4-Pyridin-3-yl-5-quinolin-4-yl-thiazol-2-ylamine	DM06AV8	Discovery agent	N.A.	Investigative	[12]
5''-Quinolin-4-yl-[2,4'']bithiazolyl-2''-ylamine	DMNYQGS	Discovery agent	N.A.	Investigative	[12]
ACE-435	DMOJGF3	Cachexia	MG20	Investigative	[13]
DRP-049	DMBUH02	Fibrosis	GA14-GC01	Investigative	[13]
GW-788388	DMIBUW5	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]
HTS-466284	DM70YTF	Discovery agent	N.A.	Investigative	[15]
IN-1130	DM3YJXF	Discovery agent	N.A.	Investigative	[16]
IN-1166	DMMS6D3	Discovery agent	N.A.	Investigative	[17]
LDN-214117	DM57Z8J	Discovery agent	N.A.	Investigative	[18]
LY2109761	DMAWTG3	Discovery agent	N.A.	Investigative	[19]
PMID16539403C15b	DMU2X59	Discovery agent	N.A.	Investigative	[20]
PMID23639540C13d	DMSTQGH	Discovery agent	N.A.	Investigative	[21]
PMID23639540C13r	DMHBZ0N	Discovery agent	N.A.	Investigative	[21]
PTL-101	DMAEL4C	Pulmonary fibrosis	CB03.4	Investigative	[13]
SB-505124	DM4G09S	Discovery agent	N.A.	Investigative	[22]
SB-525334	DM0PETL	Discovery agent	N.A.	Investigative	[22]
SD-208	DMQXUYH	Discovery agent	N.A.	Investigative	[23]
TGF-beta Shield	DMUP34S	Solid tumour/cancer	2A00-2F9Z	Investigative	[13]
WilVent	DMZ703W	Pulmonary disease	1B10-1F85	Investigative	[13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	6.95E-01	0.02	0.07
Idiopathic pulmonary fibrosis	CA23	Lung tissue	2.62E-01	0.27	1.01

References

• [1] 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.
• [2] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [3] Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov. 2004 Dec;3(12):1011-22.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Novel potent inhibitor of Bcr-Abl mutated imatinib resistant chronic myeloid leukemia cell lines. Cancer Research. 06/2012; 72(8 Supplement):1822-1822.
• [6] Targeting the TGF pathway for cancer therapy. Pharmacol Ther. 2015 Mar;147:22-31.
• [7] Clinical pipeline report, company report or official report of Sumitomo Dainippon Pharma.
• [8] Pyrazolone based TGFbetaR1 kinase inhibitors. Bioorg Med Chem Lett. 2010 Jan 1;20(1):326-9.
• [9] US patent application no. 2013,0028,978, Compositions and methods for wound treatment.
• [10] 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.
• [11] Design of novel quinazoline derivatives and related analogues as potent and selective ALK5 inhibitors. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2277-81.
• [12] Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors. J Med Chem. 2004 Aug 26;47(18):4494-506.
• [13] 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: 1788).
• [14] 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 orall... J Med Chem. 2006 Apr 6;49(7):2210-21.
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-beta type 1 receptor kina... Bioorg Med Chem. 2010 Jun 15;18(12):4459-67.
• [17] Synthesis and biological evaluation of 4(5)-(6-alkylpyridin-2-yl)imidazoles as transforming growth factor-beta type 1 receptor kinase inhibitors. J Med Chem. 2007 Jun 28;50(13):3143-7.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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).
• [23] 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.