Biology

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

Related Articles

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

Thromb Res. 2018 Aug 23;170:109-118

Authors: Clarke AS, Rousseau E, Wang K, Kim JY, Murray BP, Bannister R, Matzkies F, Currie KS, Di Paolo JA

Abstract
INTRODUCTION: 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.
MATERIAL AND METHODS: 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.
RESULTS: 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-9876 did not increase BT in humans. No in vitro additive effects on inhibition of platelet aggregation were observed with GS-9876 plus NSAIDs in human blood.
CONCLUSIONS: GS-9876 inhibited SYK activity in platelets via the GPVI receptor without prolonging BT in monkeys or humans. Furthermore, GS-9876 did not increase inhibition of platelet aggregation by NSAIDs in vitro, suggesting that these agents can potentially be combined without increasing bleeding risk in humans.

PMID: 30172129 [PubMed – as supplied by publisher]

Source link




Related posts

Multiple sclerosis: Small molecule could delay onset

Newsemia

Avian thermoregulation in the heat: is evaporative cooling more economical in nocturnal birds? [RESEARCH ARTICLE]

Newsemia

Ciliary dynein motor preassembly is regulated by Wdr92 in association with HSP90 co-chaperone, R2TP

Newsemia

This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More

Privacy & Cookies Policy