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Description: PRT062607 (also known as P505-15, BIIB-057) HCl is a novel, potent, highly selective and orally bioavailable small molecule Syk inhibitor with potential anti-inflammatory activity. It inhibits Syk with an IC50 of 1 nM in cell-free assays, and shows >80-fold selectivity for Syk over other kinases such as Fgr, Lyn, FAK, Pyk2 and Zap70. PRT062607 produced excellent in vivo anti-inflammatory activity in two rodent models of rheumatoid arthritis. P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL. PRT062607effectively antagonize CLL cell survival after BCR triggering. Moreover, they inhibit the secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell transfer toward beneath stromal cells, the tissue homing chemokines CXCL13 and CXCL12.
References: J Pharmacol Exp Ther. 2012 Feb;340(2):350-9; Leukemia. 2012 Jul;26(7):1576-83.
Related CAS: 1370261-96-3 (free base); 1370261-97-4 (HCl);
Chemical Name: 4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride
SMILES Code: O=C(C1=CN=C(N[[email protected]]2[[email protected]@H](N)CCCC2)N=C1NC3=CC=CC(N4N=CC=N4)=C3)N.[H]Cl
Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2
In vitro activity: PRT062607(P505-15) anti-SYK activity is at least 80-fold greater than its affinity for other kinases. at least 80-fold greater than its affinity for other kinases. PRT062607 potently inhibits 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). PRT062607 inhibits BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and beneath stromal cells. PRT062607 furthermore inhibits Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering
Kinase Assay: The extent of substrate phosphorylation by Syk is measured in the presence of various PRT062607 concentrations. Syk activity is determined by a fluorescent antibody specific for phosphorylated tyrosine by using the increase of FRET. Twelve concentrations are tested for dose response. Specificity and potency of kinase inhibition is determined by evaluation of PRT062607 in the Millipore KinaseProfiler panel of 270 independent purified kinase assays. For profiling, PRT062607 is tested in duplicate at two concentrations at a fixed concentration of ATP. Subsequently, IC50 determinations using the radioactive assays are carried out at an ATP concentration optimized for each individual kinase. All radioactive ATP incorporation enzyme assays are performed at Millipore.
Cell Assay: To compare the relative sensitivity of primary versus tumor B-cells, the mixing experiments in which SU-DHL6 was combined with human whole blood and treated with P505-15 were performed. Under these conditions, whereas the tumor B-cell line underwent apoptosis in response to SYK inhibition, primary B-cells did not.
J Pharmacol Exp Ther. 2012 Feb;340(2):350-9; Leukemia. 2012 Jul;26(7):1576-83.
Purity ≥ 98%
COA
MSDS
NMR
HPLC
P505-15 selectively inhibits proliferation of Syk-dependent B cell lines. J Pharmacol Exp Ther.2012 Feb;340(2):350-9.
P505-15 attenuates antibody-induced inflammation in a mouse model of rheumatoid arthritis. J Pharmacol Exp Ther.2012 Feb;340(2):350-9.
Oral administration of P505-15 significantly ameliorates the severity and development of arthritis in the rat CIA model. J Pharmacol Exp Ther. 2012 Feb;340(2):350-9.