The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction

Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1247-53. doi: 10.1161/ATVBAHA.115.306883. Epub 2016 Apr 21.

Abstract

Objective: 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.

Approach and results: 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.

Conclusions: 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.

Keywords: Syk kinase; mice; platelets; stroke; thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Arterial Occlusive Diseases / blood
  • Arterial Occlusive Diseases / enzymology
  • Arterial Occlusive Diseases / genetics
  • Arterial Occlusive Diseases / prevention & control*
  • Blood Platelets / drug effects*
  • Blood Platelets / enzymology
  • Brain / drug effects
  • Brain / enzymology
  • Brain / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fibrinolytic Agents / administration & dosage*
  • Genotype
  • Hemostasis / drug effects*
  • Infarction, Middle Cerebral Artery / blood
  • Infarction, Middle Cerebral Artery / enzymology
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / prevention & control*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Phenotype
  • Protein Kinase Inhibitors / administration & dosage*
  • Signal Transduction / drug effects
  • Syk Kinase / antagonists & inhibitors*
  • Syk Kinase / blood
  • Syk Kinase / deficiency
  • Syk Kinase / genetics
  • Thrombosis / blood
  • Thrombosis / enzymology
  • Thrombosis / genetics
  • Thrombosis / prevention & control*
  • Time Factors

Substances

  • Fibrinolytic Agents
  • Protein Kinase Inhibitors
  • Syk Kinase
  • Syk protein, mouse