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Lanraplenib (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 | C23H25N9O |
| Molecular Weight | 443.504302740097 |
| Exact Mass | 443.218 |
| CAS # | 1800046-95-0 |
| Related CAS # | Lanraplenib succinate;1800047-00-0;Lanraplenib monosuccinate;1800046-97-2 |
| PubChem CID | 118161062 |
| Appearance | Solid powder |
| LogP | 1.4 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 33 |
| Complexity | 635 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O1CC(C1)N1CCN(C2C=CC(=CC=2)NC2C3=NC=CN3C=C(C3C=NC=C(N)N=3)N=2)CC1 |
| InChi Key | XCIGZBVOUQVIPI-UHFFFAOYSA-N |
| InChi Code | 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) |
| Chemical Name | 6-(6-aminopyrazin-2-yl)-N-{4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}imidazo[1,2-a]pyrazin-8-amine |
| Synonyms | GS-9876; GS 9876; GS9876; Lanraplenib; GS-SYK |
| 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 | With EC50 values of 24-51 nM, lambranplenib (GS-9876) suppresses anti-IgM-stimulated phosphorylation of AKT, BLNK, BTK, ERK, MEK, and PKCδ in B cells. Lanraplenib (GS-9876) suppresses B cell proliferation when combined with anti-IgM/anti-CD40 (EC50=108 nM), and it also inhibits anti-IgM-mediated CD69 and CD86 expression in B cells (EC50=112 nM and 164 nM). Lanraplenib (GS-9876) prevents IC stimulation in human macrophages. Lanraplenib (GS-9876) suppresses the release of human TNFα, IL-1β, and phospholipase Cγ2, as well as the phosphorylation of T cells caused by glycoprotein VI (GPVI) (EC50=121 nM and 9 nM)[1]. In whole blood, venous activation and aggregation are paired with subarterial collagen flow [2]. |
| 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). |
| Additional Infomation |
Lanraplenib is under investigation in clinical trial NCT03285711 (Safety and Efficacy of Filgotinib and Lanraplenib in Adults With Lupus Membranous Nephropathy (LMN)). Lanraplenib is an orally available inhibitor of spleen tyrosine kinase (Syk), with potential immunomodulating and antineoplastic activities. Upon oral administration, lanraplenib binds to and inhibits the activity of Syk. This inhibits B-cell receptor (BCR) signaling, which leads to the inhibition of B-cell activation, and prevents tumor cell activation, migration, adhesion and proliferation. Syk, a non-receptor cytoplasmic, BCR-associated tyrosine kinase, is expressed in hematopoietic tissues and is often overexpressed in hematopoietic malignancies; it plays a key role in B-cell receptor signaling. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~20 mg/mL (~45.10 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (4.51 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 20.0 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 mg/mL (4.51 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 20.0 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 | 2.2548 mL | 11.2740 mL | 22.5479 mL | |
| 5 mM | 0.4510 mL | 2.2548 mL | 4.5096 mL | |
| 10 mM | 0.2255 mL | 1.1274 mL | 2.2548 mL |