Cell lines

human macrophages derived from human monocytes or the monocytic cell line THP-1

Preparation method

The solubility of this compound in DMSO is >11.75mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0-10 μM; 16 to 20 h; 37℃

Applications

In human macrophages derived from human monocytes or the monocytic cell line THP-1, R406 potently inhibited TNFα production induced by FcγR-cross-linking. Roughly 10-fold higher levels of R406 inhibited TNFα production induced by LPS.

Animal models

collagen antibody-induced arthritis (CAIA) female Balb/c mice

Dosage form

1 and 5 mg/kg; orally b.i.d for 14 days

Application

In collagen antibody-induced arthritis (CAIA) Balb/c mice, R406 reduced the cutaneous reverse passive Arthus reaction by approximately 72 and 86% at 1 and 5 mg/kg, respectively, compared with the vehicle control. R406 could inhibit local inflammatory injury mediated by immune complexs (ICs).

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

R406 is a potent SYK inhibitorSpleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase mainly expressed in hematopoietic cells. It transmits signals from a variety of cell surface receptors including CD74, Fc receptor and integrins. It is crucial for adaptive immune response, and also very important for cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. [1]

Functional abnormality of SYK has been implicated in several blood malignancies. Constitutively active SYK can transform B cells. SYK inhibition can be beneficial for patients with blood cancers and autoimmune diseases.

R406 is a potent inhibitor of IgE and IgG mediated Fc receptor activation with EC50 for degranulation of 56-64 nM. [2] R406 targets SYK and inhibits phosphorylation of SYK substrates by binding to its ATP binding pocket and competing with ATP. R406 strongly inhibits SYK kinase activity with an IC50 of 41 nM.

R406 induces apoptosis in diffuse large B-cell lymphoma cell lines. It blocks B cell receptor signaling through inhibiton of SYK autophosphorylation of Y525/Y526 and SYK-dependent phosphorylation of the B-cell linker protein. [3]

R406 can be administrated orally.

References:
[1]Mocsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010. 10(6): 387-402.
[2]Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006. 319(3): 998-1008.
[3]Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 2008. 111(4): 2230*2237.