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| Product Name: | Entospletinib (GS-9973) | | Synonyms: | GS-9973;Entospletinib;6-(1H-Indazol-6-yl)-N-[4-(4-morpholinyl)phenyl]imidazo[1,2-a]pyrazin-8-amine;GS-9973;GS 9973;CS-1602;GS9973; GS 9973; ENTOSPLETINIB;6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine;Entospletinib (GS-9973) | | CAS: | 1229208-44-9 | | MF: | C23H21N7O | | MW: | 411.46 | | EINECS: | | | Product Categories: | Inhibitors | | Mol File: | 1229208-44-9.mol |  |
| | Entospletinib (GS-9973) Chemical Properties |
| density | 1.45±0.1 g/cm3(Predicted) | | storage temp. | Desiccate at -20°C | | solubility | insoluble in EtOH; insoluble in H2O; ≥20.55 mg/mL in DMSO | | form | solid | | pka | 12.54±0.40(Predicted) |
| | Entospletinib (GS-9973) Usage And Synthesis |
| 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 (IC50 = 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). | | target | 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. |
| | Entospletinib (GS-9973) Preparation Products And Raw materials |
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