Lanraplenib (GS-9876)

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.

Product information

CAS Number: 1800046-95-0

Molecular Weight: 443.50

Formula: C23H25N9O

Synonym:

GS-SYK

Chemical Name: 6-(6-aminopyrazin-2-yl)-N-{4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}imidazo[1,2-a]pyrazin-8-amine

Smiles: NC1=CN=CC(=N1)C1=CN2C=CN=C2C(NC2C=CC(=CC=2)N2CCN(CC2)C2COC2)=N1

InChiKey: XCIGZBVOUQVIPI-UHFFFAOYSA-N

InChi: InChI=1S/C23H25N9O/c24-21-12-25-11-19(28-21)20-13-32-6-5-26-23(32)22(29-20)27-16-1-3-17(4-2-16)30-7-9-31(10-8-30)18-14-33-15-18/h1-6,11-13,18H,7-10,14-15H2,(H2,24,28)(H,27,29)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO 89 mg/mL (200.68 mM)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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.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.

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%. 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.

References:

1. J. Di Paolo, et al. Ann Rheum Dis. 2016 Jun;75:443-444.
2. Astrid S Clarke, et al. Thromb Res. 2018 Oct;170:109-118.

Products are for research use only. Not for human use.