Tamatinib(R-406) - 半岛电竞官方网址

Molecular Weight (MW)	470.45
Formula	C22H23FN6O5
CAS No.	841290-80-0 (free base);
Storage	-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)	DMSO: 21 mg/mL (44.6 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)	1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL
Synonyms	R406 besylate; R406 benzenesulfonate; Tamatinib; R 406, R406, R-406; Chemical Name: 6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one InChi Key: NHHQJBCNYHBUSI-UHFFFAOYSA-N InChi Code: InChI=1S/C22H23FN6O5/c1-22(2)20(30)28-19-13(34-22)6-7-16(27-19)26-18-12(23)10-24-21(29-18)25-11-8-14(31-3)17(33-5)15(9-11)32-4/h6-10H,1-5H3,(H3,24,25,26,27,28,29,30) SMILES Code: O=C1NC2=NC(NC3=NC(NC4=CC(OC)=C(OC)C(OC)=C4)=NC=C3F)=CC=C2OC1(C)C

Molecular Weight (MW)

470.45

Formula

C22H23FN6O5

CAS No.

841290-80-0 (free base);

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 21 mg/mL (44.6 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

Solubility (In vivo)

1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL

Synonyms

R406 besylate; R406 benzenesulfonate; Tamatinib; R 406, R406, R-406;

Chemical Name: 6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

InChi Key: NHHQJBCNYHBUSI-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H23FN6O5/c1-22(2)20(30)28-19-13(34-22)6-7-16(27-19)26-18-12(23)10-24-21(29-18)25-11-8-14(31-3)17(33-5)15(9-11)32-4/h6-10H,1-5H3,(H3,24,25,26,27,28,29,30)

SMILES Code: O=C1NC2=NC(NC3=NC(NC4=CC(OC)=C(OC)C(OC)=C4)=NC=C3F)=CC=C2OC1(C)C

In Vitro	In vitro activity: R406 is an ATP-competitive inhibitor of Syk with a Ki value of 30 nM. R406 selectively inhibits Syk-dependent signaling with EC50 values ranging from 33 nM to 171 nM, more potently than Syk-independent pathways in different cells. R406 inhibits cellular proliferation of a large panel of diffuse large B-cell lymphoma (DLBCL) cell lines at EC50 values ranging from 0.8 μM to 8.1 μM. R406 treatment (1 μM or 4 μM) induces the activation of caspases 9 and 3, but not caspase 8, leading to significant apoptosis of the majority of DLBCL cell lines. Pretreatment of R406 completely blocks the phosphorylation of SYK525/526 and the SYK-dependent phosphorylation of BLNK in R406-sensitive DLBCLs following B-cell receptor (BCR) crosslinking. R406 potently decreases MMP-9 mRNA levels by 2.8- and 4.3-fold lower than controls after 24 and 48 hours treatment, respectively, and reduces the invasive capacity of the RL cells. Kinase Assay: R406 is serially diluted in DMSO and then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL acetylated BGG). ATP and substrate in kinase buffer are added at room temperature, resulting in a final DMSO concentration on 0.2%. The kinase reactions are performed in a final volume of 20 μL containing 5 μM HS1 peptide substrate and 4 μM ATP and started by addition of 0.125 ng of Syk in kinase buffer. The reaction is allowed to proceed for 40 minutes at room temperature. The reaction is stopped by the addition of 20 μL of PTK quench mix containing EDTA/anti-phosphotyrosine antibody (1X final)/fluorescent phosphopeptide tracer (0.5X final) diluted in FP Dilution Buffer. The plate is incubated for 30 minutes in the dark at room temperature and then read on a Polarion fluorescence polarization plate reader. Data are converted to amount of phosphopeptide present using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit. For IC50 determination, R406 is tested at eleven concentrations in duplicate and curve-fitting is performed by non-linear regression analysis using Prism GraphPad Software. Cell Assay: DLBCL cell lines are treated with serial dilutions of R406 (0.3, 0.6, 1.25, 2.5, or 5 μM) for 72 or 96 hours. Thereafter, cellular proliferation is determined by MTT assay, and cell apoptosis is assessed by using annexin V–FITC/propidium iodide (PI) staining. For the determination of caspase 9, 8, and 3, cells are lysed, size-fractionated by polyacrylamide gel electrophoresis (PAGE), and immunoblotted.
In Vivo	R406 has shown efficacy in a number of animal models of immune disorders. Oral administration of R406 in mice with immune complex-mediated inflammation significantly inhibits the cutaneous reverse passive Arthus reaction by approximately 72% and 86% at 1 mg/kg and 5 mg/kg, respectively, compared with the control. R406 treatment at 10 mg/kg significantly reduces inflammation and swelling, decreases the progressive arthritis to a lower level in the passive anticollagen antibody-challenged mice, and delays the onset and reduces paw thickening and clinical arthritis by approximately 50% in the K/BxN serum transfer mice model.
Animal model	Female C57BL/6 mice challenged intravenously with 1% ovalbumin (OVA) in saline (10 mg/kg) containing 1% Evans blue dye, female Balb/c mice with the anticollagen antibody-induced arthritis, and female C57BL/6 mice with arthritis induced by intraperitoneal
Formulation & Dosage	Formulated in DMSO and diluted in saline containing 35% TPGS, 60% PEG 400, and 5% propylene glycol; 10 mg/kg; Oral gavage
References	J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008; Blood. 2008 Feb 15;111(4):2230-7.

In Vitro

In vitro activity: R406 is an ATP-competitive inhibitor of Syk with a Ki value of 30 nM. R406 selectively inhibits Syk-dependent signaling with EC50 values ranging from 33 nM to 171 nM, more potently than Syk-independent pathways in different cells. R406 inhibits cellular proliferation of a large panel of diffuse large B-cell lymphoma (DLBCL) cell lines at EC50 values ranging from 0.8 μM to 8.1 μM. R406 treatment (1 μM or 4 μM) induces the activation of caspases 9 and 3, but not caspase 8, leading to significant apoptosis of the majority of DLBCL cell lines. Pretreatment of R406 completely blocks the phosphorylation of SYK525/526 and the SYK-dependent phosphorylation of BLNK in R406-sensitive DLBCLs following B-cell receptor (BCR) crosslinking. R406 potently decreases MMP-9 mRNA levels by 2.8- and 4.3-fold lower than controls after 24 and 48 hours treatment, respectively, and reduces the invasive capacity of the RL cells.

Kinase Assay: R406 is serially diluted in DMSO and then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL acetylated BGG). ATP and substrate in kinase buffer are added at room temperature, resulting in a final DMSO concentration on 0.2%. The kinase reactions are performed in a final volume of 20 μL containing 5 μM HS1 peptide substrate and 4 μM ATP and started by addition of 0.125 ng of Syk in kinase buffer. The reaction is allowed to proceed for 40 minutes at room temperature. The reaction is stopped by the addition of 20 μL of PTK quench mix containing EDTA/anti-phosphotyrosine antibody (1X final)/fluorescent phosphopeptide tracer (0.5X final) diluted in FP Dilution Buffer. The plate is incubated for 30 minutes in the dark at room temperature and then read on a Polarion fluorescence polarization plate reader. Data are converted to amount of phosphopeptide present using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit. For IC50 determination, R406 is tested at eleven concentrations in duplicate and curve-fitting is performed by non-linear regression analysis using Prism GraphPad Software.

Cell Assay: DLBCL cell lines are treated with serial dilutions of R406 (0.3, 0.6, 1.25, 2.5, or 5 μM) for 72 or 96 hours. Thereafter, cellular proliferation is determined by MTT assay, and cell apoptosis is assessed by using annexin V–FITC/propidium iodide (PI) staining. For the determination of caspase 9, 8, and 3, cells are lysed, size-fractionated by polyacrylamide gel electrophoresis (PAGE), and immunoblotted.

In Vivo

R406 has shown efficacy in a number of animal models of immune disorders. Oral administration of R406 in mice with immune complex-mediated inflammation significantly inhibits the cutaneous reverse passive Arthus reaction by approximately 72% and 86% at 1 mg/kg and 5 mg/kg, respectively, compared with the control. R406 treatment at 10 mg/kg significantly reduces inflammation and swelling, decreases the progressive arthritis to a lower level in the passive anticollagen antibody-challenged mice, and delays the onset and reduces paw thickening and clinical arthritis by approximately 50% in the K/BxN serum transfer mice model.

Animal model

Female C57BL/6 mice challenged intravenously with 1% ovalbumin (OVA) in saline (10 mg/kg) containing 1% Evans blue dye, female Balb/c mice with the anticollagen antibody-induced arthritis, and female C57BL/6 mice with arthritis induced by intraperitoneal

Formulation & Dosage

Formulated in DMSO and diluted in saline containing 35% TPGS, 60% PEG 400, and 5% propylene glycol; 10 mg/kg; Oral gavage

References

J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008; Blood. 2008 Feb 15;111(4):2230-7.

CAS NO:	841290-80-0
规格:	≥98%

包装	价格(元)
5mg	电议
10mg	电议
25mg	电议
50mg	电议
100mg	电议
250mg	电议
500mg	电议