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Chemical Structure| 1229208-44-9 Chemical Structure| 1229208-44-9

Structure of Entospletinib
CAS No.: 1229208-44-9

Chemical Structure| 1229208-44-9

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GS-9973 is a Syk inhibitor with IC50 value of 7.7 nM which is used for the treatment of autoimmune and oncology indications.

Synonyms: GS-9973

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Product Citations

Product Citations

Nanae Asakawa ; Toshiaki Oharaseki ; Yuki Yokouchi ; Noriko Miura ; Naohito Ohno ; Kei Takahashi

Abstract: Background: The activation of innate immunity may be involved in the development of Candida albicans-induced murine vasculitis, which resembles Kawasaki disease (KD)vasculitis. This study aimed to histologically clarify the time course of the development of vasculitis in this model in detail and to estimate the potential role of spleen tyrosine kinase (Syk) inhibitors in KD vasculitis. Methods and Results: DBA/2 male mice were intraperitoneally injected with a vasculitis_x005f_x0002_inducing substance and treated with a Syk inhibitor (R788 or GS-9973). Systemic vasculitis, especially in the aortic annulus area, was histologically evaluated. Regarding lesions in the aortic annulus area, some mice in the untreated control group already showed initiation of vasculitis 1 day after the final injection of a vasculitis-inducing substance. The vasculitis expanded over time. Inflammation occurred more frequently at the aortic root than at the coronary artery. The distribution of inflammatory cells was limited to the intima, intima plus adventitia, or all layers. In the Syk inhibitor-treated groups, only one mouse had vasculitis at all observation periods. The severity and area of the vasculitis were reduced by both Syk inhibitors. Conclusion: Candida albicans-induced murine vasculitis may occur within 1 day after the injection of a vasculitis-inducing substance. Additionally, Syk inhibitors suppress murine vasculitis.

Keywords: Kawasaki disease ; vasculitis ; Candida albicans ; murine model ; Syk

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Product Details of Entospletinib

CAS No. :1229208-44-9
Formula : C23H21N7O
M.W : 411.46
SMILES Code : C12=NC=CN1C=C(C3=CC4=C(C=C3)C=NN4)N=C2NC5=CC=C(N6CCOCC6)C=C5
Synonyms :
GS-9973
MDL No. :MFCD28099806
InChI Key :XSMSNFMDVXXHGJ-UHFFFAOYSA-N
Pubchem ID :59473233

Safety of Entospletinib

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Related Pathways of Entospletinib

RTK

Isoform Comparison

Biological Activity

Target
  • Syk

    Syk, IC50:7.7 nM

In Vitro:

Cell Line
Concentration Treated Time Description References
MEC-1 cells 100 nM 96 hours GS-5829 significantly inhibits the proliferation of MEC-1 cells, but does not affect cell viability. PMC7272263
CLL cells 400 nM 120 hours GS-5829 significantly induced apoptosis in CLL cells, reducing the percentage of viable cells from 94.8% to 64.4% PMC7272263
NCI-H460/MX20 3 μM 72 hours GS-9973 reversed the drug resistance of NCI-H460/MX20 cells to mitoxantrone or doxorubicin by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the protein level but did not alter the ABCG2 mRNA expression and subcellular localization of the ABCG2 protein. PMC8315011
HEK293/ABCG2 3 μM 72 hours GS-9973 significantly increased the cytotoxicity of mitoxantrone and doxorubicin in HEK293/ABCG2 cells, reversing ABCG2-mediated multidrug resistance. PMC8315011
Mouse neutrophils 0.1 µM, 1 µM, 10 µM 10 minutes Entospletinib dose-dependently reduced the cell responses of iμMune complex- or integrin ligand-activated neutrophils, including superoxide release, cell spreading, and cytokine release. PMC10725968

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Mice GVHD model Oral 1 mM single injection Entospletinib significantly improved clinical eye scores, alopecia scores, and skin scores in GVHD mice and prolonged survival. 60% of ENTO-treated mice survived to day +120 compared with 10% of placebo-treated mice. PMC6237454
Mice K/BxN serum transfer arthritis model Oral 0.06% or 0.02% Starting from day +12 after HCT until the end of the experiment Entospletinib dose-dependently reduced the macroscopic signs of joint inflammation, while it did not affect the health status of the animals. Local neutrophil accumulation and cytokine levels were reduced, while macrophage accumulation and synovial fibroblast numbers were not significantly altered. PMC10725968

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT02521376 Oncology PHASE1 COMPLETED 2017-10-25 Clinical Pharmacology of Miami... More >>, Inc. (CPMI), Miami, Florida, United States|Orlando Clinical Research Center, Orlando, Florida, United States|DaVita Clinical Research, Minneapolis, Minnesota, United States|The Texas Liver Institute, San Antonio, Texas, United States|APEX GmBH, Munich, Germany|Auckland Clinical Studies, Auckland, New Zealand Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.43mL

0.49mL

0.24mL

12.15mL

2.43mL

1.22mL

24.30mL

4.86mL

2.43mL

References

 

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