Lanraplenib (GS-9876)

For research use only.

Catalog No.S9715 Synonyms: GS-SYK

Lanraplenib (GS-9876) Chemical Structure

CAS No. 1800046-95-0

Lanraplenib (GS-9876, GS-SYK) is a potent, highly selective and orally active inhibitor of Spleen Tyrosine Kinase (SYK) with IC50 of 9.5 nM. Lanraplenib inhibits SYK activity in platelets via the glycoprotein VI (GPVI) receptor without prolonging bleeding time (BT) in monkeys or humans.

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Biological Activity

Description Lanraplenib (GS-9876, GS-SYK) is a potent, highly selective and orally active inhibitor of Spleen Tyrosine Kinase (SYK) with IC50 of 9.5 nM. Lanraplenib inhibits SYK activity in platelets via the glycoprotein VI (GPVI) receptor without prolonging bleeding time (BT) in monkeys or humans.
Targets
GPVI receptor [2]
()
Syk [1]
(Cell-free assay)
9.5 nM
In vitro

GS-9876 inhibits anti-IgM stimulated phosphorylation of AKT, BLNK, BTK, ERK, MEK, and PKCδ in human B cells with EC50 values of 24–51 nM. Functionally, GS-9876 inhibits anti-IgM mediated CD69 and CD86 expression on B-cells (EC50=112±10 nM and 164±15 nM, respectively) and anti-IgM /anti-CD40 co-stimulated B cell proliferation (EC50=108±55 nM). In human macrophages, GS-9876 inhibits IC-stimulated TNFα and IL-1β release (EC50=121±77 nM and 9±17 nM, respectively). Anti-CD3/anti-CD28 stimulated T cell proliferation is weakly inhibited (EC50=1291±398 nM), with selectivity >10-fold versus the inhibition of B cell proliferation. In human blood, GS-9876 blocks SYK phosphorylation, CD69 expression on B cells, and CD63 expression in basophils.[1] GS-9876 inhibits glycoprotein VI (GPVI)-induced phosphorylation of linker for activation of T cells and phospholipase Cγ2, platelet activation and aggregation in human whole blood, and platelet binding to collagen under arterial flow.[2]

In vivo

GS-9876 demonstrates a dose-dependent improvement in clinical score and histopathology parameters with once-daily dosing in short and long term rat models of collagen-induced arthritis (CIA). Significant efficacy can be achieved with GS-9876 doses that produces trough pSYK inhibition of <50%.[1] Ex vivo, GPVI-stimulated platelet aggregation is inhibited in GS-9876-treated monkeys without a concomitant increase in bleeding time (BT). Similarly, orally administered GS-9876 does not increase BT in humans.[2]

Protocol

Cell Research:

[2]

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  • Cell lines: Human blood platelets
  • Concentrations: 0.01 μM to 100 μM
  • Incubation Time: 15 min
  • Method:

    Blood is preincubated for 15 min with Lanraplenib (GS-9876) and activated with ADP (0.2 μM) or convulxin (30 ng/mL) for 2 min at room temperature. Samples are stained for CD61 and CD62P, fixed, and analyzed on a FACSCanto II flow cytometer. The percentages of CD62P+ platelets are quantified and the values are subjected to nonlinear regression analysis using Prism 6 to generate EC50 values.


    (Only for Reference)
Animal Research:

[2]

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  • Animal Models: female cynomolgus monkeys
  • Dosages: 5 mg/kg, 15 mg/kg, 45 mg/kg
  • Administration: Oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 89 mg/mL (200.67 mM)
Water Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 443.50
Formula

C23H25N9O

CAS No. 1800046-95-0
Storage powder
in solvent
Synonyms GS-SYK

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT05028751 Not yet recruiting Drug: Lanraplenib|Drug: Gilteritinib Acute Myeloid Leukemia|Relapsed Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia Kronos Bio October 18 2021 Phase 1|Phase 2
NCT02959138 Completed Drug: Lanraplenib. Inflammatory Disease Gilead Sciences November 21 2016 Phase 1

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Syk Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID