Lanraplenib monosuccinate (also known as GS-9876; GS-SYK) is a highly selective and orally bioavailable Spleen Tyrosine Kinase (SYK) inhibitor with IC50 of 9.5 nM). It is currently under development by Gilead for the treatment of inflammatory diseases such as RA. Spleen Tyrosine Kinase (SYK) mediates signaling in a range of hematopoietic cells involved in the initiation and progression of RA including B cells, monocytes, macrophages, dendritic cells, and osteoclasts. There is strong preclinical validation for SYK as a therapeutic target for RA based on cellular data and animal models of disease. Lanraplenib (GS-9876) inhibits SYK activity in platelets via the glycoprotein VI (GPVI) receptor without prolonging bleeding time (BT) in monkeys or humans. GS-9876 potently inhibits multiple cellular events implicated in RA pathogenesis and displays excellent in vivo efficacy in rat CIA models after once-daily dosing. GS-9876 has markedly improved selectivity over competitor SYK programs. These data support the development of GS-9876 in inflammatory diseases, with potential for an improved safety profile.

Physicochemical Properties

Molecular Formula	C27H31N9O5
Molecular Weight	561.5923
Exact Mass	561.244
CAS #	1800046-97-2
Related CAS #	Lanraplenib;1800046-95-0;Lanraplenib succinate;1800047-00-0
PubChem CID	118161067
Appearance	Typically exists as solid at room temperature
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	13
Rotatable Bond Count	8
Heavy Atom Count	41
Complexity	728
Defined Atom Stereocenter Count	0
InChi Key	DVFRSTNNWJHWGW-UHFFFAOYSA-N
InChi Code	InChI=1S/C23H25N9O.C4H6O4/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;5-3(6)1-2-4(7)8/h1-6,11-13,18H,7-10,14-15H2,(H2,24,28)(H,27,29);1-2H2,(H,5,6)(H,7,8)
Chemical Name	6-(6-aminopyrazin-2-yl)-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine;butanedioic acid
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro

Using EC50 values of 24-51 nM, lanraplenib monosuccinate (GS-9876 monosuccinate) inhibits anti-IgM-stimulated phosphorylation of AKT, BLNK, BTK, ERK, MEK, and PKCδ in human B cells. It also 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 costimulated B-cell proliferation (EC50=108±55 nM). Finally, lanraplenib monosuccinate inhibits IC-stimulated TNFα and IL-1β release in human macrophages (EC50 121±77 nM and 9±17 nM, respectively). Finally, lanraplenib monosuccinate (GS-9876 monosuccinate) inhibits glycoprotein VI (GPVI)-induced linker phosphorylation, leading to T cell activation and phospholipase Cγ2, platelet activation and aggregati

References

[1]. FRI0049 Preclinical Characterization of GS-9876, A Novel, Oral SYK Inhibitor That Shows Efficacy in Multiple Established Rat Models of Collagen-Induced Arthritis.Annals of the Rheumatic Diseases 2016;75:443-444. [2]. Effects of GS-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis. Thromb Res. 2018 Oct;170:109-118. [3]. GS-9876, a Novel, Highly Selective, SYK Inhibitor in Patients with Active Rheumatoid Arthritis: Safety, Tolerability and Efficacy Results of a Phase 2 Study [abstract]. Arthritis Rheumatol.2018; 70 (suppl 10).

Solubility Data

Solubility (In Vitro)

DMSO : ~125 mg/mL (~222.58 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.7807 mL	8.9033 mL	17.8066 mL
	5 mM	0.3561 mL	1.7807 mL	3.5613 mL
	10 mM	0.1781 mL	0.8903 mL	1.7807 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.