R406 841290-81-1

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Molecular Weight:

628.63 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.


Biological Activity


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. 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. R406 is a potent
inhibitor of platelet signaling and functions initiated by FcγRIIA
cross-linking by specific antibodies or by sera from HIT patients.


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. R406 does not adversely affect macrophage or neutrophil
function in innate immune responses and has minimal functional
immunotoxicity notwithstanding its lymphocytopenic effect.


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)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

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)

Chemical Information

Molecular Weight (MW)	628.63
Formula	C22H23FN6O5.C6H6O3S
CAS No.	841290-81-1

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	126 mg/mL (200.43 mM)
		Water	<1 mg/mL (
		Ethanol	8 mg/mL (12.72 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

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Product Categories : Angiogenesis > Syk Inhibitor