P505-15 (also known as PRT062607) is a highly specific and potent, orally bioavailable small molecule spleen tyrosine kinase (Syk) inhibitor (IC50 = 1 nM) with anti-Syk activity that is at least 80-fold greater than its affinity for other kinases. P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 μM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 μM) in human whole blood. Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC50 0.32 μM). P505-15 (PRT062607) decreased cell viability in NHL and CLL. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations.
|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 80 mg/mL
Water 80 mg/mL
|Source||J Pharmacol Exp Ther (2013). Figure 1. P505-15|
|Cell Lines||Ramos cells|
|Incubation Time||72 h|
|Results||These data are consistent with previous observations that P505-15 is a selective and potent inhibitor of Syk, with no appreciable activity against other BCR-related kinases|
The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia.
Spurgeon SE, et al. J Pharmacol Exp Ther. 2013 Feb;344(2):378-87. PMID: 23220742.
Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis.
Coffey G, et al. J Pharmacol Exp Ther. 2012 Feb;340(2):350-9. PMID: 22040680.
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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.
R788 (Fostamatinib) is a spleen tyrosine kinase (Syk) inhibitor with IC50 of 41 nM.
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