Impact of inter-individual differences in plasma fraction unbound on the pharmacokinetics of a novel Syk kinase inhibitor in Beagle dogs

2021 ◽  
pp. DMD-AR-2021-000409
Author(s):  
Andy Pike ◽  
Barry Jones ◽  
Roshini Markandu ◽  
Daniel O'Neill
Keyword(s):  
Individual Differences ◽  
Kinase Inhibitor ◽  
Beagle Dogs ◽  
Syk Kinase ◽  
Plasma Fraction

scholarly journals Critical role of Src-Syk-PLCγ2 signaling in megakaryocyte migration and thrombopoiesis

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 793-800 ◽  
Author(s):  
Alexandra Mazharian ◽  
Steve G. Thomas ◽  
Tarvinder S. Dhanjal ◽  
Christopher D. Buckley ◽  
Steve P. Watson
Keyword(s):  
Kinase Inhibitor ◽  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Src Family Kinases ◽  
Surface Glycoprotein ◽  
Platelet Recovery ◽  
Glycoprotein Vi ◽  
Syk Kinase ◽  
And Migration

Migration of megakaryocytes (MKs) from the proliferative osteoblastic niche to the capillary-rich vascular niche is essential for proplatelet formation and platelet release. In this study, we explore the role of surface glycoprotein receptors and signaling proteins in regulating MK migration and platelet recovery after immune-induced thrombocytopenia. We show that spreading and migration of mouse primary bone marrow–derived MKs on a fibronectin matrix are abolished by the Src family kinases inhibitor PP1, the Syk kinase inhibitor R406 and the integrin αIIbβ3 antagonist lotrafiban. We also demonstrate that these responses are inhibited in primary phospholipase C γ2 (PLCγ2)–deficient MKs. Conversely, MK spreading and migration were unaltered in the absence of the collagen receptor, the glycoprotein VI–FcRγ-chain complex. We previously reported a correlation between a defect in MK migration and platelet recovery in the absence of platelet endothelial cell adhesion molecule-1 and the tyrosine phosphatase CD148. This correlation also holds for mice deficient in PLCγ2. This study identifies a model in which integrin signaling via Src family kinases and Syk kinase to PLCγ2 is required for MK spreading, migration, and platelet formation.

Identification of the Syk kinase inhibitor R112 by a human mast cell screen

2006 ◽  
Vol 118 (3) ◽  
pp. 749-755 ◽  
Author(s):  
A ROSSI ◽  
E HERLAAR ◽  
S BRASELMANN ◽  
S HUYNH ◽  
V TAYLOR ◽  
...  
Keyword(s):  
Mast Cell ◽  
Kinase Inhibitor ◽  
Human Mast Cell ◽  
Syk Kinase

scholarly journals Treatment of rheumatoid arthritis with a syk kinase inhibitor: A twelve-week, randomized, placebo-controlled trial

2008 ◽  
Vol 58 (11) ◽  
pp. 3309-3318 ◽  
Author(s):  
Michael E. Weinblatt ◽  
Arthur Kavanaugh ◽  
Ruben Burgos-Vargas ◽  
Ara H. Dikranian ◽  
Gabriel Medrano-Ramirez ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitor ◽  
Controlled Trial ◽  
Syk Kinase

Thrombopoietin stimulates cortactin translocation to the cytoskeleton independently of tyrosine phosphorylation

2001 ◽  
Vol 356 (3) ◽  
pp. 875-881 ◽  
Author(s):  
Isabelle LOPEZ ◽  
Véronique DUPREZ ◽  
Josiane MELLE ◽  
François DREYFUS ◽  
Sylviane LÉVY-TOLÉDANO ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Kinase Inhibitor ◽  
Shape Change ◽  
Insoluble Fraction ◽  
Actin Binding ◽  
Syk Kinase ◽  
Tyrosine Phosphorylated Protein ◽  
Triton X ◽  
Cortactin Tyrosine Phosphorylation ◽  
Platelet Shape

Cortactin is an F-actin-binding protein expressed in platelets. During aggregation by thrombin, cortactin associates with Src, is tyrosine phosphorylated, and then translocates to the cytoskeleton. It is also found to associate with Syk during platelet shape change. Since cortactin undergoes tyrosine phosphorylation in platelets activated by thrombopoietin (TPO) that exhibit neither shape change nor aggregation, we investigated whether it could also relocalize to the detergent-insoluble fraction. We demonstrate that cortactin was present as a tyrosine-phosphorylated protein and co-localized with Syk in the Triton X-100-insoluble fraction of TPO-activated platelets. TPO stimulated Syk activation and association with cortactin. Conversely, cortactin associated with the kinases, Syk and Src. Cortactin tyrosine phosphorylation was blocked by Syk kinase inhibitor, piceatannol or Src family kinase inhibitor, PP2, suggesting that it depends on these two kinases. However, piceatannol or PP2 did not prevent cortactin translocation to the detergent-insoluble fraction. These data suggest that tyrosine phosphorylation is not required for cortactin translocation to the detergent-insoluble compartment. Furthermore, TPO activates, through its receptor c-Mpl, a signalling pathway to the cytoskeleton.

Inhibition of Hepatobiliary Transporters by A Novel Kinase Inhibitor Contributes to Hepatotoxicity in Beagle Dogs

2013 ◽  
Vol 7 (1) ◽  
pp. 15-22 ◽  
Author(s):  
John Daniels ◽  
Yurong Lai ◽  
Sarah South ◽  
Po-Chang Chiang ◽  
Daniel Walker ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Beagle Dogs
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