R406 is an orally bioavailable and selective inhibitor of spleen tyrosine kinase (Syk) with the IC50 of 41nM and Ki value of 30 nM. R406 is an active component of its prodrug R788 or R935788 (Fostamatinib).
|Cell lines||CLL cells|
|Preparation method||To evaluate the effect of BCR stimulation on CLL cell viability, CLL cells (107/mL) were incubated in complete RPMI medium (control) or in complete medium supplemented with 10 μg/mL anti-IgM (polyclonal goat F(ab′)2 fragments to human IgM [MP Biomedicals] at 37°C in 5% CO2). After 24 and 48 hours, CLL cell viability was measured by analysis of mitochondrial transmembrane potential by 3,3 dihexyloxocarbocyanine iodine (DiOC6; Invitrogen-Molecular Probes) and cell membrane permeability to propidium iodide (PI; Molecular Probes), as described.13 Briefly, 200 μL cell suspension was collected at the indicated time points and transferred to fluorescence-activated cell sorter tubes containing 200 μL of 60 nM DiOC6 and 2 μg/mL PI in RPMI with 0.5% bovine serum albumin. Cells were then incubated at 37°C for 15 minutes and analyzed within 30 minutes by flow cytometry on a FACSCalibur (BD Biosciences).|
|Incubation time||24 and 48 h|
|Animal models||K/BxN Model in C57BL/6 mice|
|Formulation||35% TPGS, 60% PEG 400, and 5% propylene glycol|
|Dosages||b.i.d for 13 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO ≥29 mg/mL|
B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406.
Quiroga MP, et al. Blood. 2009 Jul 30;114(5):1029-37. PMID: 19491390.
Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases.
Bajpai M. IDrugs. 2009 Mar;12(3):174-85. PMID: 19333898.
R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation.
Braselmann S, et al. J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008. PMID: 16946104.
|Related Syk Products|
PRT-060318 (PRT318) is a novel selective inhibitor of the Syk tyrosine kinase, as an approach to HIT treatment.
BAY-61-3606 is a potent and selective inhibitor of Syk kinase (Ki = 7.5 nM).
Piceatannol, a natural stilbene, is a selective Syk inhibitor and ~10-fold selectivity versus Lyn.
GS-9973 is an orally bioavailable, selective Syk inhibitor with IC50 of 7.7 nM.
P505-15 (PRT062607) is a novel, highly selective inhibitor of Syk with IC50 value of 1-2 nM.
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