The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction.
Ischemic stroke, which is mainly caused by thromboembolic occlusion of brain arteries, is the second leading cause of death and disability worldwide with limited treatment options. The platelet collagen receptor glycoprotein VI (GPVI) is a key player in arterial thrombosis and a critical determinant of stroke outcome, making its signaling pathway an attractive target for pharmacological intervention. The spleen tyrosine kinase (Syk) is an essential signaling mediator downstream of not only GPVI but also other platelet and immune cell receptors. We sought to assess whether Syk might be an effective antithrombotic target.



We demonstrate that mice lacking Syk in platelets specifically are protected from arterial thrombus formation and ischemic stroke but display unaltered hemostasis. Furthermore, we show that mice treated with the novel, selective, and orally bioavailable Syk inhibitor BI1002494 were protected in a model of arterial thrombosis and had smaller infarct sizes and a significantly better neurological outcome 24 hours after transient middle cerebral artery occlusion, also when BI1002494 was administered therapeutically, that is, after ischemia.



These results provide direct evidence that pharmacological Syk inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and to limit infarct progression in acute stroke.
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
Judith M M
JM
van Eeuwijk
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
David
D
Stegner
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
David J
DJ
Lamb
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
Peter
P
Kraft
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
Sarah
S
Beck
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
Ina
I
Thielmann
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
Friedemann
F
Kiefer
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
Barbara
B
Walzog
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.).
Guido
G
Stoll
From the Department of Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.) and Department of Neurology (P.K., G.S.), University Hospital Würzburg and Rudolf Virchow Center for Experimental Biomedicine (J.M.M.v.E., D.S., S.B., I.T., B.N.), University of Würzburg, Würzburg, Germany; Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany (D.J.L.); Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany (F.K.); and Walter Brendel Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, Ludwig Maximilian University of Munich, Munich, Germany (B.W.). bernhard.nieswandt@virchow.uni-wuerzburg.de.
Bernhard
B
Nieswandt
D000284:Administration, Oral; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D005838:Genotype; D006487:Hemostasis / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000172:deficiency / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D013997:Time Factors
D005343:Fibrinolytic Agents; D047428:Protein Kinase Inhibitors; D000072377:Syk Kinase; C000606897:Syk protein, mouse
Syk kinase; mice; platelets; stroke; thrombosis