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PRT-060318

Names

[ CAS No. ]:
1194961-19-7

[ Name ]:
PRT-060318

[Synonym ]:
2-{[(1R,2S)-2-Aminocyclohexyl]amino}-4-[(3-methylphenyl)amino]-5-pyrimidinecarboxamide
PRT318
2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide
P142–76
5-Pyrimidinecarboxamide, 2-[[(1R,2S)-2-aminocyclohexyl]amino]-4-[(3-methylphenyl)amino]-
PRT 060318

Biological Activity

[Description]:

PRT-060318 (PRT318) is a novel selective inhibitor of the tyrosine kinase Syk with an IC50 of 4 nM.

[Related Catalog]:

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Syk
Research Areas >> Cancer

[Target]

IC50: 4 nM (Syk)[1]


[In Vitro]

PRT318 is a potent inhibitor of purified Syk kinase with an IC50 of 4 nM. Syk kinase is inhibited by 92%, whereas all other kinases retains more than 70% at a concentration of 50 nM of PRT318[1]. PRT318 and P505-15 effectively antagonize CLL cell survival after B-cell receptor (BCR) triggering and in nurse-like cell-co-cultures. They inhibit 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. PRT318 and P505-15 inhibit Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering[2].

[In Vivo]

PRT318 completely inhibits HIT immune complex-induced aggregation of both human and transgenic HIT mouse platelets. Pretreatment of mice with PRT318 markedly reduces HIT IC-induced thrombosis in the lungs. The Thrombosis Score is significantly lower for PRT318-treated mice compared with control[1].

[Cell Assay]

PRT318 is dissolved in DMSO. Cells are incubated for 14 days in 24-well plates. CLL cells are cultured under standardized conditions on NLC or in suspension, in the presence or absence of PRT318 and P505-15. At 24, 48, 72 h, CLL cells are collected and assayed for cell viability[2].

[Animal admin]

Mice: Heparin-induced thrombocytopenia (HIT) model mice are treated with KKO (20 mg/kg body weight, intraperitoneally) on day 0. The mice are divided into sex- and weight-matched experimental and control groups. On days 1 to 7, experimental mice (n=6) receives PRT318 (30 mg/kg body weight) orally via gavage twice a day, whereas control mice (n=6) receives vehicle only (sterile water). Both groups receives heparin (1600 U/kg body weight, subcutaneously) once daily. Mice are anesthetized by isoflurane inhalation for injections and blood collections[1].

[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.


[Related Small Molecules]

Entospletinib | cerdulatinib | Piceatannol | BAY-61-3606 | R788 (disodium hexahydrate) | R406 | PRT062607 (P505-15, BIIB057) HCl | TAK-659 hydrochloride | RO9021 | ASN-002 | MDBN | R 112

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
602.1±65.0 °C at 760 mmHg

[ Molecular Formula ]:
C18H24N6O

[ Molecular Weight ]:
340.423

[ Flash Point ]:
317.9±34.3 °C

[ Exact Mass ]:
340.201172

[ PSA ]:
118.95000

[ LogP ]:
1.62

[ Vapour Pressure ]:
0.0±1.7 mmHg at 25°C

[ Index of Refraction ]:
1.672

Related Compounds