Description
Entospletinib (GS-9973) is an orally bioavailable, selective Syk inhibitor with IC50 of 7.7 nM in a cell-free assay and showed 13-to >1000-fold cellular selectivity for Syk over other kinases(including Jak2, ckit, Flt3, Ret, KDR) as assessed by target protein phosphorylation or functional response.
Features
Orally bioavailable Syk-selective inhibitor that has been tested in Phase II clinical trials for treatment of Haematological Malignancies.
In vitro
GS-9973 shows good bidirectional permeability across Caco-2 cell monolayers in vitro. In cells, GS-9973 also shows excellent selectivity for Syk, and potently inhibits BCR-mediated activation and proliferation of B-cells as well as immune-complex-stimulated cytokine production in monocytes. The combination of idelalisib and GS-9973 synergistically inhibits CLL cell viability and further disrupts chemokine signaling.
In vivo
GS-9973 (1 mg/kg p.o.) shows moderate to high bioavailability in rat and dog. In a rat collagen-induced arthritis model, GS-9973 (1-10 mg/kg p.o.) significantly inhibits ankle inflammation. Moreover, GS-9973 also shows disease-modifying activity in multiple histological measurements, including inhibition of pannus formation, cartilage damage, bone resorption, and peritosteal bone formation with ED50 ranging from 1.2 to 3.9 mg/kg .
Description
Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase that upon phosphorylation binds to immunoreceptor tyrosine-based activation motifs of FcRγ chains and mediates downstream signaling related to platelet function and inflammation. GS-9973 is a potent Syk inhibitor (IC
50 = 7.7 nM) that demonstrates 10-35-fold selectivity for Syk over a panel of 359 nonmutant kinases. In conjunction with the PI3Kδ inhibitor CAL-101 , it has been used to reduce chronic lymphocytic leukemia cell survival and to disrupt chemokine signaling at nanomolar concentrations.
Uses
GS 9973 is a selective and orally bioavailable inhibitor of spleen tyrosine kinase (Syk).
References
[1]. currie ks, kropf je, lee t, et al. discovery of gs-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. j med chem, 2014, 57(9): 3856-3873.
[2]. burke rt1, meadows s, loriaux mm, et al. a potential therapeutic strategy for chronic lymphocytic leukemia by combining idelalisib and gs-9973, a novel spleen tyrosine kinase (syk) inhibitor. oncotarget, 2014, 5(4): 908-915.
[3]. sharman j, hawkins m, kolibaba k, et al. an open-label phase 2 trial of entospletinib (gs-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. blood, 2015, 125(15): 2336-2343.
