In vitro: PRT318 inhibits platelet activation via GPVI/FcRγ, an ITAM receptor complex, but not via ADP or thrombin, which are G-protein coupled receptors. PRT318 effectively antagonizes CLL(chronic lymphocytic leukemia) cell survival after BCR triggering and in nurse-like cell-co-cultures. PRT318 inhibits Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering.
In vivo: In both rabbit and pig models, intravenous infusion of PRT060318 targets maximal inhibition of Syk kinase activity and significantly inhibits arterial thrombosis. The antithrombotic activity of PRT060318 in pigs is remarkable because it was achieved with complete inhibition of CVXN-induced platelet aggregation, with no effect on ADP-induced platelet aggregation, and no prolongation of ear bleeding time.
Also, Syk inhibitor PRT318 is an active agent in HIT. Inhibition of Syk signaling with the orally bio-available PRT318 limits the thrombocytopenic and thrombotic effects of HIT IC in vivo.
|Cell lines||LY3，LY4，LY7,LY18 cell lines|
|Preparation method||The numbers of cells treated with various doses of PRT318 are followed over time. PRT318 inhibits growth of the sensitive cell lines in a dose-dependent manner. Two sensitive (LY7 and LY18) and 2 resistant (LY3 and LY4) cell lines are treated with indicated doses of PRT318.|
|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||75 mg/mL in DMSO|
Src family kinases and Syk are required for neutrophil extracellular trap formation in response to β-glucan particles.
Nanì S, et al. J Innate Immun. 2015;7(1):59-73. PMID: 25277753.
PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model.
Reilly MP, et al. Blood. 2011 Feb 17;117(7):2241-6. PMID: 21088136.
|Related Syk Products|
R112 is an ATP-competitive inhibitor of Syk kinase with an IC50 of 226 nM.
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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