TGF-β receptors (Transforming growth factor-β receptors) are single pass serine/threonine kinase receptors. Transforming growth factor beta (TGF-beta) is a member of a large family of pleiotropic cytokines that are involved in many biological processes, including growth control, differentiation, migration, cell survival, adhesion, and specification of developmental fate, in both normal and diseased states. TGF-beta superfamily members signal through a receptor complex comprising a type II and type I receptor, both serine/threonine kinases.
The type I receptors, referred to as activin receptor-like kinases (ALK), lie at the epicenter of the signaling cascade as they transduce TGF-beta signals to intracellular regulators of transcription known as Smad proteins. ALKs possess an extracellular binding domain, a transmembrane domain, a GS domain that serves as the site of activation by type II receptors, and a kinase domain that activates downstream signaling molecules. ALKs mediate the effect of TGF-beta superfamily on a variety of cellular processes such as proliferation, differentiation, apoptosis, adhesion and migration, and therefore play important roles in many biological processes. Some ALKs have been implicated in several disorders, including tumorigenesis and immune diseases, suggesting that these receptors can be used as drug targets.
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LY 3200882 (LY3200882) is a novel potent, highly selective, ATP competitive TGF-β receptor type 1 (TGFβRI, ALK5) inhibitor; potently inhibits TGFβ mediated SMAD phosphorylation in vitro in tumor and immune cells and in vivo in subcutaneous tumors; LY 3200882 shows potent anti-tumor activity in the orthotopic 4T1-LP model of triple negative breast cancer and this activity correlated with enhanced tumor infiltrating lymphocytes in the tumor microenvironment.
AZ12601011 (AZ-12601011) is a potent, selective inhibitor of ALK4, ALK7 and TGFBR1 (Kd=2.9 nM), inhibits TGFβ-induced reporter activity with IC50 of 18 nM; inhibits TGFBR1 kinase activity (competition binding) with Kd of 2.9 nM, shows some inhibitory activity against the related receptors ALK4 and BMPR1B, but shows only weakly activity against ALK1, ALK2 and BMPR1A in in vitro kinase assays; AZ12601011 is a more effective inhibitor of TGFβ-induced reporter activity than SB-431542 (IC50=84nM) and LY2157299 (galunisertib) (IC50=380nM), inhibits phosphorylation of SMAD2 via the type 1 receptors ALK4, TGFBR1 and ALK7; AZ12601011 is highly effective at inhibiting basal and TGFβ-induced migration of HaCaT keratinocytes, inhibits tumour growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumour model.
AZ12799734 (AZ-12799734) is a pan BMP/TGFβ inhibitor that potently inhibits ligand activated SMAD3/4 transcription with IC50 of 47 nM, inhibits receptor-mediated phosphorylation of SMAD1 by ALK1, BMPR1A and BMPR1B and phosphorylation of SMAD2 by ALK4, TGFBR1 and ALK7; inhibits TGFβ-induced migration in HaCaT cells.
BMP signaling agonist sb4
BMP signaling agonist sb4 is a small molecule BMP signaling agonist with EC50 of 73.6 nM, enhances the efficacy of BMPs and activates endogenous BMP4 target genes; increases the phosphorylation of key second messengers (SMADs-1/5/9) and also increased expression of direct target genes (inhibitors of DNA binding, ID1 and ID3) in canonical BMP signaling.
ML347 (LDN 193719) is a potent, highly selective ALK2 inhibitor with IC50 of 32 nM, also inhibits ALK1 (IC50=46 nM) and shows no activity against ALK3/4/5/6, and BMPR2,TGFBR2; ML347 is potent in the BMP4 cell assay (152 nM) as well as the in vitro kinase assay for ALK1 (46 nM) and ALK2 (32 nM) and is devoid of activity in a number of related kinases.
FT-011 is a novel anti-fibrotic agent that prevents TGF-beta-stimulated production of collagen in cultured renal mesangial cells (55-70% inhibition at 30 uM); inhibits both TGF-β1 and PDGF-BB induced collagen production as well as PDGF-BB-mediated mesangial proliferation, attenuates the decline in GFR, proteinuria and glomerulosclerosis in a robust model of non-diabetic kidney disease; attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy.
A potent and selective ALK2 inhibitor with a biochemical IC50 of 24 nM, a cell-based IC50 for BMP6 of 100 nM; displays 164-fold selectivity for BMP6 versus TGF-β1; a highly selective probes of BMP-mediated cellular physiology.
A potent, selective TGF-beta type I receptor ALK-5, ALK-4 and ALK-7 inhibitor with IC50 of 12, 45 and 7.5 nM, respectively; dispalys weak or no inhibitory activity again transcriptional activity of ALK6 and ALK1/2/3; prevents phosphorylation of Smad2/3 and the growth inhibition induced by TGF-beta with no effects on BMP signaling, ERK and p38 MAPK.
R-268712 is a potent, selective, orally active inhibitor of TGF-β type I receptor ALK5 with IC50 of 2.5 nM, >5,000-fold more selectivity than p38 MAPK; inhibits the development of renal fibrosis in a dose-dependent manner in a unilateral ureteral obstruction (UUO) model at doses of 1, 3 and 10mg/kg, also reduces proteinuria and glomerulosclerosis significantly with improvement of renal function in glomerulonephritis models.
K02288 is a potent, selective inhibitor of BMP signaling with IC50 of 1.8/1.1/34.4/6.3 nM for ALK/1/2/3/6, displays 300-fold selectivity for ALK2 over the TGF-β receptor ALK5 and ALK4; also wekaly inhibits type II BMP receptor ActRIIA (IC50=220 nM); specifically inhibits the BMP-induced Smad pathway without affecting TGF-β signaling and induces dorsalization of zebrafish embryos; inhibits BMP9-induced phosphorylation of SMAD1/5/8 in HUVECs to reduce both the SMAD and the Notch-dependent transcriptional responses, inhibits functional angiogenesis.
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