product name Entospletinib (GS-9973)
Description: Entospletinib (also known as GS-9973) is an orally available, highly selective Syk inhibitor with IC50 of 7.7 nM in a cell-free assay. Entospletinib is currently undergoing clinical evaluation for autoimmune and oncology indications. In Phase II clinical trials, Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. In monocytes, GS-9973 inhibited immune-complex-stimulated cytokine production and BCR-mediated proliferation and activation of B-cells. In chronic lymphocytic leukemia (CLL) cells, GS-9973 significantly reduced pAkt and ribosomal S6 phosphorylation. These results suggested that GS-9973 inhibited B-cell receptor (BCR) mediated signaling pathways.
References: J Med Chem. 2014 May 8;57(9):3856-73; Oncotarget. 2014 Feb 28;5(4):908-15.
411.46
Formula
C23H21N7O
CAS No.
1229208-44-9
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 82 mg/mL (199.3 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
4% DMSO+30% PEG 300+5% Tween 80+ddH2O: 2.5 mg/mL
Synonyms
GS-9973
other peoduct :
| In Vitro |
In vitro activity: 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. Kinase Assay: Full-length baculovirus-expressed Syk kinase activity is measured in a Lance-based assay format in a final volume of 25 μL containing 25 mM Tris–HCl, pH 7.5, 5 mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na3VO4, 10 mM MgCl2, 0.5 μM Promega PTK biotinylated peptide substrate 1, 0.01% casein, 0.01% Triton X-100, 0.25% glycerol, and 40 mM ATP (Km for ATP) incubated at room temperature for 60 min. Reactions are stopped with the addition of 30 mM EDTA containing 30 μL of SA-APC and 4 nM PT-66 antibody and the plates measured on a Perkin-Elmer Envision. IC50 values for test compounds are determined using a four-parameter linear regression algorithm. Cell Assay: Functional impact on cellular Flt3 activity is determined by measuring compound inhibition of MV-4-11 cell proliferation. A total of 104 cells are diluted in RPMI medium containing 10% FBS in 96-well flat-bottomed tissue culture plates and incubated with compound dilutions for 72 h at 37 °C. Alamar blue (10%) is added to the cells, which were incubated for an additional 12-18 h at 37 °C, and inhibition of the relative cell numbers is determined by spectrophotometer readings at 570/600 nm. |
|---|---|
| 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. |
| Animal model | Rat Collagen-Induced Arthritis (CIA) Model |
| Formulation & Dosage | Dissolved in Cremophor/ethanol/saline;10 mg/kg; oral administration |
| References | J Med Chem. 2014 May 8;57(9):3856-73; Oncotarget. 2014 Feb 28;5(4):908-15. |
