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

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

  • Thromb Res. 2018 Oct;170:109-118. doi: 10.1016/j.thromres.2018.08.012.
Astrid S Clarke 1,  Emma Rousseau 2,  Kelly Wang 3,  Ji-Yun Kim 4,  Bernard P Murray 5,  Roy Bannister 6,  Franziska Matzkies 7,  Kevin S Currie 8,  Julie A Di Paolo 9
Affiliations

Affiliations

  • 1 Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: astrid.clarke@gilead.com.
  • 2 Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
  • 3 Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: kelly.wang@gilead.com.
  • 4 Biomarker Sciences, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: ji-yun.kim@gilead.com.
  • 5 Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: bernard.murray@gilead.com.
  • 6 Drug Safety Evaluation, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: roy.bannister@gilead.com.
  • 7 Clinical Research, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: franziska.matzkies@gilead.com.
  • 8 Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: kevin.currie@gilead.com.
  • 9 Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States. Electronic address: julie.dipaolo@gilead.com.
PMID: 30172129 DOI: 10.1016/j.thromres.2018.08.012
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.

Keywords

Bleeding time; Glycoprotein VI receptor; Hemostasis; Nonsteroidal anti-inflammatory drugs (NSAIDs); Platelet; Spleen tyrosine kinase (SYK).

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