**Background**
Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays a critical role in signal transduction for various immune cells, including B cells, mast cells, and macrophages. By mediating the signaling of immunoreceptors, SYK is essential for the activation of immune responses and the production of pro-inflammatory cytokines. Dysregulation of SYK signaling is implicated in numerous pathological conditions, ranging from autoimmune diseases and chronic inflammation to certain hematological malignancies. Consequently, the development of potent and selective SYK inhibitors has become a significant focus for treating inflammatory disorders and certain types of cancer. In this context, we will introduce a highly selective SYK inhibitor – GSK143.
**Definition**
GSK143 is an orally active and highly selective spleen tyrosine kinase (SYK) inhibitor with a pIC50 of 7.5.
**In Vitro and In Vivo Studies**
According to the GSK143 description, this compound also inhibits phosphorylated Erk (pErk) with a pIC50 of 7.1. In terms of GSK143 in vitro activity, the compound demonstrates selectivity over other kinases, including ZAP-70 (pIC50 = 4.7), LCK (pIC50 = 5.3), LYN (pIC50 = 5.4), and JAK1/2/3 (pIC50 = 5.8/5.8/5.7). In chronic lymphocytic leukaemia (CLL) cells, GSK143 (10-10,000 nM; every 24 hours for 3 days) exhibited an IC50 of 323 nM. Furthermore, treatment with 1 μM GSK143 for 30 minutes abrogated early signaling events, including SYK phosphorylation and calcium flux. In bone marrow-derived macrophages, concentrations of 0.1-10 μM for 30 minutes reduced cytokine expression in a concentration-dependent manner.
Regarding GSK143 In Vivo efficacy, the compound has shown significant potential in reducing inflammation. In wild-type C57NL/BL6 mice, oral administration of GSK143 (0.1-10 mg/kg; 1.5 hours before intestinal manipulation) reduced inflammation and prevented the recruitment of immune cells in the intestinal muscularis. In male CD rats, GSK143 (3, 10, 30, 100 mg/kg; oral; 1 hour before ovalbumin challenge) reduced the cutaneous reverse passive Arthus reaction in a dose-dependent manner, achieving approximately 50% and 70% reduction at 10 mg/kg and 30 mg/kg, respectively. Pharmacokinetic analysis in rats indicated that GSK143 (iv 1 mg/kg; po 3 mg/kg) has a T1/2 of 4.2 hours, low clearance (16 mL/min/kg), and moderate bioavailability of 30%. For researchers seeking detailed GSK143 technical information, these results highlight its potency as an oral therapeutic agent. In conclusion, GSK143 is a potent, selective, and orally efficacious SYK inhibitor suitable for research in inflammation and GSK143 Cancer studies.
Keywords
GSK143, 2341796-81-2, GSK 143, GSK-143, Syk, ERK, Spleen tyrosine kinase, Extracellular signal regulated kinases, orally, spleen, tyrosine, kinase, phosphorylated, inflammation, ZAP-70
References
[1] John Liddle, et al. Discovery of GSK143, a Highly Potent, Selective and Orally Efficacious Spleen Tyrosine Kinase Inhibitor. Bioorg Med Chem Lett. 2011 Oct 15;21(20):6188-94.
[2] Abraham M Varghese, et al. Highly Selective SYK Inhibitor, GSK143, Abrogates Survival Signals in Chronic Lymphocytic Leukaemia. Br J Haematol. 2018 Sep;182(6):927-930.
[3] Sjoerd H W van Bree, et al. Inhibition of Spleen Tyrosine Kinase as Treatment of Postoperative Ileus. Gut. 2013 Nov;62(11):1581-90.