| GS-9973Syk inhibitor, orally bioavailable and selective |
Sample solution is provided at 25 µL, 10mM.
Nature.2017 Jan 19;541(7637):417-420.
Nature.2018 Nov;563(7731):407-411.Nature.2018 Jun 13.Nature.2018 Jun 27.Nature.2018 Mar 29;555(7698):673-677.Nature.2017 Sep 7;549(7670):96-100.Nature.2016 Apr 21;532(7599):398-401.
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- Purity = 98.22%
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Chemical structure
| Description | GS-9973 is an orally bioavailable, selective inhibitor of Syk with IC50 value of 7.7 nM. | |||||
| Targets | Syk | |||||
| IC50 | 7.7 nM | |||||
| Kinase experiment [1]: | |
Kinase assays | Full-length baculovirus-expressed Syk kinase activity was 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 mins. Reactions were stopped with the addition of 30 mM EDTA containing 30 μL of SA-APC and 4 nM PT-66 antibody and the plates were measured on a Perkin-Elmer Envision. IC50 values for test compounds were determined using a four-parameter linear regression algorithm. |
| Cell experiment [1]: | |
Cell lines | MV-4-11 cells |
Preparation method | The solubility of this compound in DMSO is > 20.6 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
Reacting condition | 10 μM; 72 hrs |
Applications | GS-9973 selectively inhibited Syk in cells, and potently suppressed BCR-mediated activation and proliferation of B-cells as well as immune-complex-induced cytokine production in monocytes. |
| Animal experiment [1]: | |
Animal models | Rat collagen-induced arthritis (CIA) model |
Dosage form | 1 ~ 10 mg/kg; p.o.; b.i.d. |
Applications | In a rat CIA model, GS-9973 (1 ~ 10 mg/kg; p.o.; b.i.d.) significantly reduced ankle inflammation. Moreover, GS-9973 also showed disease-modifying activity in several histological measurements, including inhibition of pannus formation, cartilage damage, bone resorption, as well as periosteal bone formation with the ED50 values ranging from 1.2 to 3.9 mg/kg. |
Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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. | |
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| Cas No. | 1229208-44-9 | SDF | Download SDF |
| Chemical Name | 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine | ||
| Canonical SMILES | C12=NC=CN1C=C(C3=CC=C(C=NN4)C4=C3)N=C2NC5=CC=C(N6CCOCC6)C=C5 | ||
| Formula | C23H21N7O | M.Wt | 411.46 |
| Solubility | ≥20.55mg/mL in DMSO | Storage | Desiccate at -20°C |
| Physical Appearance | A solid | Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size:ship with RT , or blue ice upon request |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
GS-9973 is a selective inhibitor of Syk with IC50 value of 7.7 nM [1].
Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase that is expressed mainly in hematopoietic cells and acts as a mediator of immunoreceptor signaling. Syk can be used for therapy of autoimmune, oncology indications and allergy [1].
GS-9973 is an orally bioavailable and selective Syk inhibitor. GS-9973 showed good absorption potential and high bioavailability. In monocytes, GS-9973 inhibited immune-complex-stimulated cytokine production and BCR-mediated proliferation and activation of B-cells [1]. 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. In CLL samples, the combination of GS-9973 and idelalisib synergistically reduced CLL cell viability [2].
In chronic lymphocytic leukemia patients, GS-9973 inhibited adenopathy and reduced lymph node [3].
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.
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