R406

R406 is a potent Syk inhibitor with IC50 of 41 nM, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 1.

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R406 Chemical Structure

R406 Chemical Structure
Molecular Weight: 628.63

Validation & Quality Control

Customer Reviews(1)

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Product Information

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  • R406 Mechanism

Product Description

Biological Activity

Description R406 is a potent Syk inhibitor with IC50 of 41 nM, strongly inhibits Syk but not Lyn, 5-fold less potent to Flt3. Phase 1.
Targets Flt3 [1] Syk [1]
IC50 41 nM
In vitro R406 is a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling. R406 inhibits the anti-IgE-induced production and release of LTC4 and cytokines and chemokines, including TNFα, IL-8, and GM-CSF. R406 inhibits phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 binds to the ATP binding pocket of Syk and inhibits its kinase activity as an ATP-competitive inhibitor with Ki of 30 nM. R406 blocks Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and Bcr-mediated activation of B lymphocytes. [1] R406 significantly induces chronic lymphocytic leukemia (CLL) cell apoptosis in nurselike cells cocultures and blocks CCL3 and CCL4 secretion by CLL cells in response to B-cell antigen receptor (Bcr) triggering. [2] R406 is a potent inhibitor of platelet signaling and functions initiated by FcγRIIA cross-linking by specific antibodies or by sera from HIT patients. [3]
In vivo R406 reduces cutaneous reverse passive Arthus reaction by approximately 86% at 5 mg/kg in prophylactic treated mice. R406 also shows efficacy in inhibiting paw inflammation in antibody-induced arthritis mouse models. [1] R406 does not adversely affect macrophage or neutrophil function in innate immune responses and has minimal functional immunotoxicity notwithstanding its lymphocytopenic effect. [4]
Features Lead drug candidate for rheumatoid arthritis.

Protocol(Only for Reference)

Kinase Assay: [1]

In Vitro Fluorescence Polarization 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 mL containing 5mM HS1 peptide substrate, 4 mM 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 mL 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 and curve-fitting is performed by non-linear regression analysis.
Ki Determination For Ki determination, duplicate 200-μL reactions are set up at eight different ATP concentrations from 200 μM (2-fold serial dilutions) in the presence of either DMSO or R406 at 125, 62.5, 31.25, 15.5, or 7.8 nM. At different time points, 20 μL

Animal Study: [1]

Animal Models Arthritis is induced in C57BL/6 mice by intraperitoneal injection of 150 μL of pooled sera from adult K/BxN mice.
Formulation 35% TPGS, 60% PEG 400, and 5% propylene glycol
Dosages 1 or 5 mg/kg
Administration Administered orally
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Braselmann S, et al. J Pharmacol Exp Ther, 2006, 319(3), 998-1008.

[2] Quiroga MP, et al. Blood, 2009, 114(5), 1029-1037.

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Chemical Information

Download R406 SDF
Molecular Weight (MW) 628.63
Formula

C22H23FN6O5.C6H6O3S

CAS No. 841290-81-1
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 126 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol 8 mg/mL (12 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one benzenesulfonate

Research Area

Customer Reviews (1)


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Rating
Source Clin Cancer Res, 2013, 19(3), 586-597. R406 purchased from Selleck
Method Annexin V/PI staining
Cell Lines Z-138/JEKO-1 cells
Concentrations 2.5/5 µM
Incubation Time 48 h
Results The combination was found to be considerably more potent than each agent alone in both cell lines, with CI values of 0.594 and 0.560 for the combination of sorafenib 5 µM with R406 2.5 and 5 µM respectively for Z-138, and 0.551 and 0.586 for JEKO-1 (Figure 1C). Importantly, this effect was also found in primary MCL cells, where combination of sorafenib (7.5 and 10 µM) with R406 (2.5 and 5 µM) revealed a strong synergy in all the samples studied (n= 7), with a mean CI of 0.681 and 0.648 for the combination of sorafenib 7.5 µM with R406 2.5 and 5 µM respectively, and 0.635 and 0.611 with sorafenib 10 µM (Figure D).

Product Citations (5)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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