1229208-44-9

Basic information

• 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;6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine;Entospletinib (GS-9973);GS-9973, Entospletinib;Entospletinib Dimesylate;6-(1H-indazol-6-yl)-N-(4-morpholin-4-ylphenyl)imidazo[1,2-a]pyrazin-8-amine
• CAS NO: 1229208-44-9
• Molecular Formula: C₂₃H₂₁N₇O
• Molecular Weight: 411.45914
• EINECS: -0
• Product Categories: Inhibitors
• Mol File: 1229208-44-9.mol
• Article Data: 2

Chemical Properties

• Appearance: /
• Density: 1.45±0.1 g/cm3(Predicted)
• Solubility: insoluble in EtOH; insoluble in H2O; ≥20.55 mg/mL in DMSO
• PKA: 12.54±0.40(Predicted)
• CAS DataBase Reference: Entospletinib (GS-9973)(CAS DataBase Reference)
• NIST Chemistry Reference: Entospletinib (GS-9973)(1229208-44-9)
• EPA Substance Registry System: Entospletinib (GS-9973)(1229208-44-9)

Safety Data

• Hazardous Substances Data: 1229208-44-9(Hazardous Substances Data)

Usage

Description

Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk) with an IC50 of 7.7 nM in a cell-free assay. It exhibits 13-to >1000-fold cellular selectivity for Syk over other kinases, such as Jak2, ckit, Flt3, Ret, and KDR. Syk is a non-receptor tyrosine kinase that plays a crucial role in platelet function, inflammation, and immune responses. Entospletinib demonstrates potent Syk inhibition (IC50 = 7.7 nM) and 10-35-fold selectivity for Syk over a panel of 359 nonmutant kinases.

Uses

Used in Pharmaceutical Industry:
Entospletinib (GS-9973) is used as a Syk inhibitor for the treatment of various conditions related to platelet function and inflammation. Its high selectivity and potency make it a promising candidate for therapeutic applications in this field.
Used in Chronic Lymphocytic Leukemia (CLL) Treatment:
Entospletinib (GS-9973) is used in combination with the PI3Kδ inhibitor CAL-101 to reduce CLL cell survival and disrupt chemokine signaling at nanomolar concentrations. This combination therapy aims to enhance the efficacy of treatment for patients with CLL.
Used in Inflammation and Immune Response Modulation:
Entospletinib (GS-9973) is used as a Syk inhibitor to modulate downstream signaling related to inflammation and immune responses. By targeting Syk, it can potentially be employed in the treatment of conditions involving dysregulated immune responses or excessive inflammation.

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 .

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.

Upstream product

• 937049-58-6 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 
• 445263-72-9 6-bromo-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine 

Relevant articles and documents

Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase

Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.