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.
|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|
|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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
|Solubility||DMSO 80 mg/mL
Water 80 mg/mL
 Spurgeon SE, et al. J Pharmacol Exp Ther. 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.
|Related Syk Products|
GSK2646264 is a potent and selective splenic tyrosine kinase (Syk) inhibitor with a pIC50 value of 7.1. GSK2646264 also inhibited other kinases, with pIC50 values of 5.4, 5.4, 5.3, 5, 4.5, <4.6 and <4.3 for LCK, LRRK2, GSK3β, JAK2, VEGFR2, Aurora B and Aurora A, respectively. GSK2646264 penetrates into the epidermis and dermis of the skin.
Lanraplenib (GS-9876, GS-SYK) is a potent, highly selective and orally active inhibitor of Spleen Tyrosine Kinase (SYK) with IC50 of 9.5 nM. Lanraplenib inhibits SYK activity in platelets via the glycoprotein VI (GPVI) receptor without prolonging bleeding time (BT) in monkeys or humans.
SRX3207 is an orally active dual inhibitor of Syk-PI3K with IC50 of 39.9 nM, 31200 nM, 3070 nM, 3070 nM, 244 nM, 388 nM, 9790 nM for Syk, Zap70, BRD41, BRD42, PI3K alpha, PI3K delta, PI3K gamma, respectively. SRX3207 blocks tumor immunosuppression and increases anti-tumor immunity.
RO9021 potently inhibits SYK kinase activity with an average IC50 of 5.6 nM and suppresses B-cell receptor signaling.
WAY-321341 is a syk inhibitor
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