title: Critical role for Syk in responses to vascular injury.
abstract: Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet-dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.
authors: Portola Pharmaceuticals Inc, South San Francisco, CA, USA.
authors: Patrick
authors: P
authors: Andre
authors: Toshifumi
authors: T
authors: Morooka
authors: Derek
authors: D
authors: Sim
authors: Keith
authors: K
authors: Abe
authors: Clifford
authors: C
authors: Lowell
authors: Nisha
authors: N
authors: Nanda
authors: Suzanne
authors: S
authors: Delaney
authors: Gail
authors: G
authors: Siu
authors: Yibing
authors: Y
authors: Yan
authors: Stan
authors: S
authors: Hollenbach
authors: Anjali
authors: A
authors: Pandey
authors: Huiyun
authors: H
authors: Gao
authors: Yunmei
authors: Y
authors: Wang
authors: Kohsuke
authors: K
authors: Nakajima
authors: Sahil A
authors: SA
authors: Parikh
authors: Can
authors: C
authors: Shi
authors: David
authors: D
authors: Phillips
authors: Whyte
authors: W
authors: Owen
authors: Uma
authors: U
authors: Sinha
authors: Daniel I
authors: DI
authors: Simon
mesh_terms: D000818:Animals; D003514:Cyclohexylamines / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine; D000072377:Syk Kinase; D013927:Thrombosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D057772:Vascular System Injuries / Q000235:genetics / Q000503:physiopathology* / Q000534:rehabilitation; D014945:Wound Healing / Q000235:genetics*
chemical_list: C569036:2-(2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide; D003514:Cyclohexylamines; D047908:Intracellular Signaling Peptides and Proteins; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse