Spleen tyrosine kinase (Syk) is an intracellular cytoplasmic tyrosine kinase that mediates immunoreceptor signaling primarily in hematopoietic cells. GS-9973 is a potent, selective, and orally bioavailable Sky inhibitor with an EC50 value of 26 nM[1]. The level of phosphorylated Akt and ribosomal S6 in primary chronic lymphocytic leukemia (CLL) cells was decreased by 100 nM GS-9973 compared to control cells, while idelalisib and GS-9973 in combination (100 nM each) showed more potent inhibitory effect on Akt and ribosomal S6 phosphorylation. Compared to single agent treatment, the combination of GS-9973 (0.01 - 10 μM) and idelalisib (0.01 - 10 μM) synergistically decreased the cell viability of CLL cells isolated from the peripheral blood or bone marrow[2]. In a rat collagen-induced arthritis model, twice daily oral dosing with GS-9973 at 10, 3, and 1 mg/kg significantly inhibited ankle inflammation. Histological analyses showed that GS-9973 inhibited cartilage damage, bone resorption, pannus formation, and peritosteal bone formation with ED50 values ranging from 1.2 to 3.9 mg/kg[1].
作用机制
GS-9973 is a selective, orally efficacious, imidazopyrazine-based inhibitor of Syk that forms a hydrogen bond with the D512 side chain of Syk kinase[1].
Entospletinib 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
C57BL/6 mouse bone marrow cells
Cytotoxic assay
4 days
Cytotoxicity against C57BL/6 mouse bone marrow cells assessed as growth inhibition preincubated for 4 days followed by [3H]-thymidine addition measured after 5 hrs by betaplate counting analysis, IC50=0.582 μM
25633741
human MV411 cells
Proliferation assay
72 h
Inhibition of Flt3 in human MV411 cells assessed as assessed as proliferation after 72 hrs incubation by spectrophotometry, EC50=0.327 μM
Cytotoxicity against C57BL/6 mouse bone marrow cells assessed as growth inhibition preincubated for 4 days followed by [3H]-thymidine addition measured after 5 hrs by betaplate counting analysis, IC50=0.582 μM
25633741
human MV411 cells
Proliferation assay
72 h
Inhibition of Flt3 in human MV411 cells assessed as assessed as proliferation after 72 hrs incubation by spectrophotometry, EC50=0.327 μM
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