Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function.

Article Details

Citation

Zheng TJ, Lofurno ER, Melrose AR, Lakshmanan HHS, Pang J, Phillips KG, Fallon ME, Kohs TCL, Ngo ATP, Shatzel JJ, Hinds MT, McCarty OJT, Aslan JE

Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function.

Am J Physiol Cell Physiol. 2021 May 1;320(5):C902-C915. doi: 10.1152/ajpcell.00296.2020. Epub 2021 Mar 10.

PubMed ID
33689480 [ View in PubMed
]
Abstract

Spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating intracellular immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK have been developed as antineoplastic and anti-inflammatory therapeutics and have also gained interest as antiplatelet agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to collagen, dense granule secretion, and alpha granule secretion in response to the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Similarly, these TKIs reduced the percentage of activated integrin alphaIIbbeta3 on the platelet surface in response to CRP-XL, as determined by PAC-1 binding. Although all TKIs tested inhibited phospholipase C gamma2 (PLCgamma2) phosphorylation following GPVI-mediated activation, other downstream signaling events proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially affected. In addition, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered the organization of PI3K around microtubules during platelets spreading on fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
BranebrutinibTyrosine-protein kinase BTKProteinHumans
Unknown
Inhibitor
Details
EntospletinibTyrosine-protein kinase SYKProteinHumans
Unknown
Inhibitor
Details
FenebrutinibTyrosine-protein kinase BTKProteinHumans
Unknown
Inhibitor
Details
FostamatinibTyrosine-protein kinase SYKProteinHumans
Yes
Inhibitor
Details
IbrutinibTyrosine-protein kinase BTKProteinHumans
Yes
Inhibitor
Details
SpebrutinibTyrosine-protein kinase BTKProteinHumans
Unknown
Inhibitor
Details
TamatinibTyrosine-protein kinase SYKProteinHumans
Unknown
Inhibitor
Details
TirabrutinibTyrosine-protein kinase BTKProteinHumans
Unknown
Inhibitor
Details