4-[4-(2H-1,3-benzodioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl]benzamide

• ChemBase ID: 72489
• Molecular Formular: C22H16N4O3
• Molecular Mass: 384.38744
• Monoisotopic Mass: 384.12224039
• SMILES: c1cccc(n1)c1[nH]c(nc1c1cc2c(cc1)OCO2)c1ccc(cc1)C(=O)N
• Canonical SMILES: NC(=O)c1ccc(cc1)c1[nH]c(c(n1)c1ccc2c(c1)OCO2)c1ccccn1
• InChI: InChI=1S/C22H16N4O3/c23-21(27)13-4-6-14(7-5-13)22-25-19(20(26-22)16-3-1-2-10-24-16)15-8-9-17-18(11-15)29-12-28-17/h1-11H,12H2,(H2,23,27)(H,25,26)
• InChIKey: FHYUGAJXYORMHI-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-[4-(2H-1,3-benzodioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl]benzamide
• IUPAC Traditional name: 4-[4-(2H-1,3-benzodioxol-5-yl)-5-(pyridin-2-yl)-1H-imidazol-2-yl]benzamide
• Synonyms: SB 431542

Database IDs

• CAS Number: 301836-41-9
• PubChem SID: 162037414
• PubChem CID: 4521392

CALCULATED PROPERTIES

• Acid pKa: 11.000039
• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): 3.0923889
• LogD (pH = 7.4): 3.1214204
• Log P: 3.1218998
• Molar Refractivity: 116.2087 cm^3
• Polarizability: 43.732277 Å^3
• Polar Surface Area: 103.12 Å^2
• Rotatable Bonds: 4
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: ALK

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1067

Research Area

• Description: Cancer

Biological Activity

• Description: SB 431542 is a potent and selective inhibitor of ALK5 with IC50 of 94 nM.
• Targets: ALK5
• IC50: 94 nM ^[1]
• In Vitro: SB 431542 inhibits the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are responsible for the phosphorylation of Smad2. SB 431542 has little effect on ALK1, ALK2, ALK3, and ALK6, which show phosphorylation of Smad1. SB 431542 is a selective inhibitor of endogenous activin but has no apparent effect on BMP signaling. SB 431542 could induce both Smad2/Smad4- and Smad3/Smad4-dependent transcription. ^[2] In A498 cells, SB 431542 inhibits both TGF-β1–induced collagen Iα1 and PAI-1 mRNA with IC50 values of 60 and 50 nM, respectively. In addition, SB 431542 inhibits production of TGF-β1–induced fibronectin mRNA and protein with IC50 of 62 and 22 nM, respectively. ^[3] SB 431542 blocks the TGF-β–mediated growth factors, including PDGF-A, FGF-2 and HB-EGF, leading to an increase in proliferation of MG63 cells. SB 431542 also inhibits TGF-β–induced c-Myc and p21 ^WAF1/CIP1. ^[4] SB 431542 significantly suppresses TGF-β–induced G1 arrest, leading to accumulation of cells in the S phase of the cell cycle in FET, RIE, and Mv1Lu cells. SB 431542 also inhibits TGF-β-induced epithelial to mesenchymal transition (EMT) in NMuMG and PANC-1 cells. ^[5] SB 431542 significantly elevates the expression of CD86 in BM-DCs and that of CD83 within CD11c+ cells suppressed by TGF-β. SB 431542 is able to induce NK activity through functional maturation and IL-12 production of human DCs. ^[6]
• In Vivo: SB 431542 triggers cytotoxic T lymphocyte (CTL) activities in the colon-26 carcinoma models and is most likely to produce antitumor immunological outcomes through alteration of DC function suppressed by TGF-β. ^[6]

Protocol

• Protocol: Kinase Assay ^[1]
• Flashplate assay for ALK5: SB 431542 is dissolved in DMSO at a concentration of 10 mM. The kinase domain of TGFβRI, from amino acid 200 to the C-terminus, and the full-length Smad3 protein are expressed as N-terminal glutathion S-transferase (GST) fusion proteins in the baculovirus expression system. Proteins are purified with glutathion Sepharose beads 4B. Basic FlashPlates are coated with 0.1 M sterile filtered sodium bicarbonate, pH 7.6, containing 700 ng of GST-Smad3 per 100 μL. Assay buffer contains 50 mM HEPES (pH 7.4), 5 mM MgCl₂, 1 mM CaCl₂, 1 mM DTT, 100 mM GTP, 3 μM ATP plus 0.5 μCi/well ?^33P-ATP, and 85 ng of GST-ALK5 with or without SB 431542. Plates are incubated at 30 °C for 3 hours. The assay buffer is removed by aspiration, and the plate is counted on a Packard TopCount 96-well scintillation plate reader.
• Protocol: Cell Assay ^[4]
• Cell Lines: MG63 and NIH3T3
• Concentrations: 0.3 μM
• Incubation Time: 30 minutes
• Methods: To explore the effects of ligands, MG63 and NIH3T3 cells are seeded at a density of 8 × 10^4 cells/well in 6-well plates and starved (0.1% FCS for MG63 cells and 0.5% FCS for NIH3T3 cells) for 24 hours before ligand stimulation. Media containing various ligands are exchanged at 48-hours intervals. Cells are trypsinized and counted by a Coulter counter on days 2, 4, and 6 after ligand stimulation. To explore the effects of constitutively active receptors, cells are seeded at a density of 2 × 10^5 cells/well in 6-well plates. The next day, cells are infected with adenoviruses carrying various cDNAs at a multiplicity of infection of 100. Cells are trypsinized and counted on day 3. Cell proliferation assay is performed in the presence of 0.3 μM SB 431542.
• Protocol: Animal Study ^[6]
• Animal Models: BALB/c mice receive intraperitoneal (i.p.) injections of colon-26 tumor cells.
• Formulation: DMSO
• Doses: 1 μM solution, 100 μL/mouse
• Administration: Directly injected into peritoneal cavity

References

• References: [1] Callahan JF, et al. J Med Chem, 2002, 45(5), 999-1001.
• References: [2] Inman GJ, et al. Mol Pharmacol, 2002, 62(1), 65-74.
• References: [3] Laping NJ, et al. Mol Pharmacol, 2002, 62(1), 58-64.
• References: [4] Matsuyama S, et al. Cancer Res, 2003, 63(22), 7791-7798.
• References: [5] Halder SK, et al. Neoplasia, 2005, 7(5), 509-521.
• References: [6] Tanaka H, et al. Oncol Rep, 2010, 24(6), 1637-1643.

REFERENCES

• Tanaka H, et al. Oncol Rep, 2010, 24(6), 1637-1643.
• Callahan JF, et al. J Med Chem, 2002, 45(5), 999-1001.
• Inman GJ, et al. Mol Pharmacol, 2002, 62(1), 65-74.
• Laping NJ, et al. Mol Pharmacol, 2002, 62(1), 58-64.
• Matsuyama S, et al. Cancer Res, 2003, 63(22), 7791-7798.
• Halder SK, et al. Neoplasia, 2005, 7(5), 509-521.