Effects of GS-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis

Thrombosis Research
Astrid S ClarkeJulie A Di Paolo

Abstract

Spleen tyrosine kinase (SYK) mediates signal transduction in multiple hematopoietic cells, including platelets. SYK signals downstream of immunoreceptors and SYK inhibition may ameliorate disease pathology in multiple autoimmune disorders; however, the impact of SYK inhibition in platelets and its potential relevance to bleeding is not fully understood. These studies evaluated the effect of an oral SYK inhibitor, GS-9876, on platelets in vitro and in vivo, and the impact of GS-9876 plus non-steroidal anti-inflammatory drugs (NSAIDs) on platelet aggregation. The effect of GS-9876 on platelet activation, aggregation, and binding was characterized by western blotting, aggregometry, fluorescence-activated cell sorting, and microscopy techniques. The effect of GS-9876 on in vivo bleeding time (BT) was determined in cynomolgus monkeys and humans. GS-9876 inhibited glycoprotein VI (GPVI)-induced phosphorylation of linker for activation of T cells and phospholipase Cγ2, platelet activation and aggregation in human whole blood, and platelet binding to collagen under arterial flow. Ex vivo, GPVI-stimulated platelet aggregation was inhibited in GS-9876-treated monkeys without a concomitant increase in BT. Similarly, orally administered GS...Continue Reading

References

Jul 26, 1996·The Journal of Biological Chemistry·J GibbinsS P Watson
May 9, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·F ColucciJ P Di Santo
Aug 25, 2001·The New England Journal of Medicine·S YusufUNKNOWN Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
Jan 9, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Christine SedlikSebastian Amigorena
Nov 30, 2004·Zeitschrift für Kardiologie·M Merten, P Thiagarajan
Sep 2, 2006·The Journal of Pharmacology and Experimental Therapeutics·Sylvia BraselmannEsteban S Masuda
Jun 1, 2007·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Polly R PineErnest Brahn
May 15, 2010·Nature Reviews. Immunology·Attila MócsaiVictor L J Tybulewicz
Aug 18, 2010·The Journal of Experimental Medicine·Hervé FaletJohn H Hartwig
Sep 2, 2011·Blood·Patrick AndreDaniel I Simon
Jun 26, 2012·The EMBO Journal·Sebastian KönigsbergerFriedemann Kiefer
Nov 30, 2013·British Journal of Haematology·Alan T Nurden, Paquita Nurden
Dec 3, 2013·The Journal of Clinical Investigation·Paul R HessMark L Kahn
May 2, 2014·Journal of Medicinal Chemistry·Kevin S CurrieScott A Mitchell
Jul 31, 2014·Annals of the Rheumatic Diseases·Peter C TaylorMichael Weinblatt
Oct 9, 2014·International Journal of Molecular Sciences·Reinaldo Barros GeraldoHelena Carla Castro
Dec 3, 2014·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Angel LanasLuis A García-Rodríguez
Apr 23, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Judith M M van EeuwijkBernhard Nieswandt

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.