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PRT-060318 (also known as PRT318) is a novel, potent, selective inhibitor of the Syk tyrosine kinase, as an approach to HIT treatment. PRT-060318 was identified as a potent inhibitor of purified Syk kinase. Syk kinase was inhibited by 92%, while the activities all other kinases retained more than 70% when PRT-060318 were evaluated at a concentration of 50 nM in a broad panel of kinase enzyme assays. In addition, PRT-060318 could dose-responsively inhibited convulxin-induced human PRP aggregation. Moreover, it was found that PRT-060318 was able to dose-responsively inhibit the increases in intracellular calcium in convulxin-treated platelets.
| ln Vitro |
With an IC50 of 4 nM, PRT318 is a strong inhibitor of pure Syk kinase. At a dose of 50 nM of PRT318, Syk kinase is inhibited by 92%, whereas the other kinases retain more than 70%[1]. PRT318 and P505-15 successfully inhibit the survival of CLL cells in nurse-like cell co-cultures and upon B-cell receptor (BCR) activation. They prevent leukemia cells from migrating toward the tissue-homing chemokines CXCL12, CXCL13, and underneath stromal cells, as well as the BCR-dependent release of the chemokines CCL3 and CCL4 by CLL cells. Following BCR triggering, PRT318 and P505-15 block the phosphorylation of Syk and extracellular signal-regulated kinase[2].
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| ln Vivo |
Human and transgenic HIT mouse platelets are completely inhibited from aggregating by the HIT immune complex when PRT318 is present. Mice pretreated with PRT318 have significantly less lung thrombosis caused by HIT IC. Mice treated with PRT318 had a significantly lower Thrombosis Score than the control group [1].
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| References |
[1]. Reilly MP, et al. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood. 2011 Feb 17;117(7):2241-6.
[2]. Hoellenriegel J, et al. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia. 2012 Jul;26(7):1576-83 |
| Molecular Formula |
C18H24N6O
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| Molecular Weight |
340.42
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| CAS # |
1194961-19-7
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| SMILES |
O=C(C1=CN=C(N[ C@H]2[C@@H](N)CCCC2)N=C1NC3=CC=CC(C)=C3)N
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| Synonyms |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 25 mg/mL (73.44 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9375 mL | 14.6877 mL | 29.3755 mL | |
| 5 mM | 0.5875 mL | 2.9375 mL | 5.8751 mL | |
| 10 mM | 0.2938 mL | 1.4688 mL | 2.9375 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Platelet function studies. (A) Aggregation of human PRP was done to compare the effect of PRT318 on convulxin versus ADP.Blood.2011 Feb 17;117(7):2241-6. |
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HIT IC-mediated platelet aggregation in vitro. (A) Human PRP (250 000 platelets/μL) was incubated at 37°C for 15 minutes with aliquots of a mixture of PF4 and heparin (1.5:1 molar ratio) containing 5 μg PF4.Blood.2011 Feb 17;117(7):2241-6. |
HIT IC-mediated thrombocytopenia in vivo.Blood.2011 Feb 17;117(7):2241-6. |
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