SB 431542 is a potent and selective inhibitor of the TGF-β1 receptor ALK5 with an IC50 of 94 nM, and its relatives ALK4 and ALK7. It does not affect the BMP receptors ALK2, ALK3, ALK6, or a panel of other kinases tested. SB 431542 specifically blocks Smad signaling, reducing gene expression relevant to fibrosis and cancer. Suppresses TGF-β-induced proliferation of human osteosarcoma cells.
|Cell lines||human DCs|
|Preparation method||Effects of SB-431542 on murine BM-DCs and human DCs. DCs were incubated in 96-well plates (5x104 cells/200 μl/well) with SB-431542 or vehicle alone and LPS in the presence of LPS at different concentrations in triplicates, and then examined for expression of co-stimulatory molecules using FACSCalibur. After 24 h of incubation, the cells were examined for surface expression of CD86 or CD83 within the CD11c+ populations, and the supernatants were tested for cytokine production by enzyme-linked immunosorbent assay (ELISA). Following 24 h of incubation with a test drug, BM-DCs were incubated for 10 min with 5 mg/ml of fluorescein isothiocyanate (FITC)-conjugated dextran (DX) (70,000 Dalton molecular weight, Sigma) at 4˚C or 37˚C, washed extensively, and then examined for FITC signals by CD11c+ cells. After drug pretreatment, BM-DC preparations (derived from BALB/c mice) were washed 3 times and then co-cultured in 96 round-bottom well plates at 4 different cell densities (0.3-10x103 cells/well) with splenic T cells purified from C57BL/6 mice (5x104 cells/well). The magnitude of T cell proliferation was assessed by 3H-thymidine uptake on day 4. Human DC cultures derived from PBMCs were examined for surface phenotype within the CD11c+ population and cytokine production by ELISA as well as for allogeneic mixed lymphocyte reaction.|
|Incubation time||24 hr|
|Animal models||BALB/c mice received intraperitoneal (i.p.) injections of colon-26 tumor cells|
|Dosages||1 μM (100μL)|
|Administration||directly injected into peritoneal cavity|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Differential signalling through ALK-1 and ALK-5 regulates leptin expression in mesenchymal stem cells.
Zeddou M, et al. Stem Cells Dev. 2012 Jul 20;21(11):1948-55. PMID: 22087763.
Activation of the activin A-ALK-Smad pathway in systemic sclerosis.
Takagi K, et al. J Autoimmun. 2011 May;36(3-4):181-8. PMID: 21377836.
Transforming growth factor β1 down-regulates Runx-2 and alkaline phosphatase activity of human dental pulp cells via ALK5/Smad2/3 signaling.
Lin PS, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Mar;111(3):394-400. PMID: 21236710.
Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity.
Tanaka H, et al. Oncol Rep. 2010 Dec;24(6):1637-43. PMID: 21042762.
|Related ALK Products|
LDK378 2Hcl (Ceritinib) is potent inhibitor against ALK with IC50 of 0.2 nM, shows 40- and 35-fold selectivity against IGF-1R and InsR, respectively.
Entrectinib (RXDX-101) is an orally bioavailable pan-TrkA/B/C, ROS1 and ALK inhibitor with IC50 ranging between 0.1 and 1.7 nM. Phase 2.
Crizotinib is inhibitor of the c-Met kinase and the NPM-ALK. Crizotinib inhibited cell proliferation in ALK-positive ALCL cells (IC50s=30 nM). Crizotinib is useful in treatment of anaplastic large-cell lymphoma.
Brigatinib (AP26113) is a potent and selective ALK (IC50, 0.6 nM) and ROS1 (IC50, 0.9 nM) inhibitor. It also inhibits ROS1, FLT3, and mutant variants of FLT3 (D835Y) and EGFR with lower potentcy.
ALK-IN-1 is an analog of AP26113 which is a potent and selective ALK inhibitor. It is also an inhibitor of EGFR.
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