SD-208

Names

[ Name ]:
SD-208

[Synonym ]:
ALK5 Inhibitor V
2-(5-chloro-2-fluorophenyl)-N-(pyridin-4-yl)pteridin-4-amine
2-(5-Chloro-2-fluorophenyl)-N-(4-pyridinyl)-4-pteridinamine
SD-208
4-Pteridinamine, 2-(5-chloro-2-fluorophenyl)-N-4-pyridinyl-
SD208

Biological Activity

[Description]:

SD-208 is a selective TGF-βRI (ALK5) inhibitor with IC50 of 48 nM, and > 100-fold selectivity over TGF-βRII.

[Related Catalog]:

Signaling Pathways >> TGF-beta/Smad >> TGF-β Receptor

Research Areas >> Cancer

[Target]

IC50: 48 nM (TGF-βRI)

[In Vitro]

SD-208 inhibits the cell growth and constitutive and TGF-beta-evoked migration and invasion, and enhances immunogenicity in murine SMA-560 and human LN-308 glioma cells[1]. SD-208 blocks TGF-beta-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, and stimulates epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro[2]. SD-208 also abolishes the promoting effect of TGF-β on neointimal smooth muscle-like cell (SMLC) proliferation and migration in vitro[3].

[In Vivo]

SD-208 (1 mg/mL, p.o.) significantly prolongs the median survival of SMA-560 glioma-bearing mice[1]. In syngeneic 129S1 mice, SD-208 (60 mg/kg/d, p.o.) inhibits primary R3T tumor growth, and reduces the number and the size of lung metastases[2]. In the murine aortic allograft model, SD-208 effectively reduces the formation of intimal hyperplasia of transplant arteriosclerosis (TA)[3].

[Kinase Assay]

Various kinase activities are assayed by measuring the incorporation of radiolabeled ATP into a peptide or protein substrate. The reactions are performed in 96-well plates and included the relevant kinase, substrate, ATP, and appropriate cofactors. The reactions are incubated and then stopped by the addition of phosphoric acid. Substrate is captured onto a phosphocellulose filter, which is washed free of unreacted ATP. The counts incorporated are determined by counting on a microplate scintillation counter. The ability of SD-208 to inhibit the respective kinase is determined by comparing counts incorporated in the presence of compound with those incorporated in the absence of compound.

[Cell Assay]

Glioma cells are cultured in the absence or presence of SD-208 (1 μM) for 48 hours. The cells are pulsed for the last 24 hours with [methyl-3H]thymidine (0.5 μCi) and harvested, and incorporated radioactivity is determined in a liquid scintillation counter.

[Animal admin]

VM/Dk mice are purchased from the TSE Resource Center. Mice of 6 to 12 weeks of age are used for the survival experiments. Groups of eight mice are anesthesized before all intracranial procedures and placed in a stereotaxic fixation device. A burr hole is drilled in the skull 2 mm lateral to the bregma. The needle of a Hamilton syringe is introduced to a depth of 3 mm. SMA-560 cells [5×103cells] resuspended in a volume of 2 μL of PBS are injected into the right striatum. Three days later, the mice are allowed to drink SD-208 at 1 mg/mL in deionized water. The mice are observed daily and, in the survival experiments, sacrificed on development of neurologic symptoms.

[References]

[1]. Uhl M, et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 2004 Nov 1;64(21):7954-61.

[2]. Ge R, et al. Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4315-30.

[3]. Sun Y, et al. Inhibition of intimal hyperplasia in murine aortic allografts by the oral administration of the transforming growth factor-beta receptor I kinase inhibitor SD-208. J Heart Lung Transplant. 2014 Jun;33(6):654-61.

[Related Small Molecules]

SB431542 | Galunisertib (LY2157299) | A 83-01 | LY2109761 | LDN193189 | RepSox | SB525334 | Vactosertib (TEW-7197) | DMH-1 | GW788388 | LY364947 | SB505124 | LY3200882 | H-Leu-Ser-Lys-Leu-NH2 trifluoroacetate salt | ITD-1

Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Boiling Point ]:
460.4±45.0 °C at 760 mmHg

[ Molecular Formula ]:
C₁₇H₁₀ClFN₆

[ Molecular Weight ]:
352.753

[ Flash Point ]:
232.2±28.7 °C

[ Exact Mass ]:
352.063965

[ PSA ]:
76.48000

[ LogP ]:
2.69

[ Appearance of Characters ]:
off-white to tan

[ Vapour Pressure ]:
0.0±1.1 mmHg at 25°C

[ Index of Refraction ]:
1.717

[ Storage condition ]:
2-8°C

[ Water Solubility ]:
DMSO: >5mg/mL

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS07

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H302

[ Personal Protective Equipment ]:
dust mask type N95 (US);Eyeshields;Gloves

[ Hazard Codes ]:
Xn

[ Risk Phrases ]:
22

[ RIDADR ]:
NONH for all modes of transport

Articles

Inhibition of Transforming Growth Factor-β (TGF-β) Signaling by Scutellaria baicalensis and Fritillaria cirrhosa Extracts in Endometrial Cancer.

J. Cell. Biochem. 116 , 1797-805, (2015)

Transforming growth factor-β (TGF-β), regulates cell proliferation, angiogenesis, metastasis, and is an inducer of epithelial-mesenchymal transition (EMT). Cancer cells exhibit activated TGF-β/SMAD si...

Differential TGF-{beta} signaling in retinal vascular cells: a role in diabetic retinopathy?

Invest. Ophthalmol. Vis. Sci. 51(4) , 1857-65, (2010)

Purpose. An early hallmark of preclinical diabetic retinopathy is thickening of the capillary basal lamina (BL). TGF-beta, a multipotent cytokine acting through its receptors ALK5 and -1, has been pos...

SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo.

Cancer Res. 64 , 7954-7961 , (2004)

The cytokine transforming growth factor (TGF)-beta, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment of human malignant gliomas....