GSK143 is an Orally Active and Highly Selective Spleen Tyrosine Kinase (SYK) Inhibitor

Tyrosine-protein kinase SYK is an enzyme which in humans is encoded by the SYK gene. Specifically, Syk is a 72 kDa cytoplasmic non-receptor tyrosine kinase and it is relevant to in a variety of signal transduction cell types. Besides, Syk and ZAP-70, which are related to the zeta chain, are the only members of the Syk protein-tyrosine family. Moreover, Syk mediates a variety of cell responses, including proliferation, differentiation, and phagocytosis, by coupling activated immune receptors with downstream events. Furthermore, Syk mediated immunosuppression signaling leads to inhibition of mast cell, macrophage and B cell activation and subsequent release of inflammatory regulators. Therefore, the discovery of safe small molecule Syk inhibitors has attracted many people’s attention in many therapeutic fields. It includes the treatment of rheumatoid arthritis, B-cell lymphoma, the occurrence of asthma/rhinitis. GSK143 is an orally active and highly selective spleen tyrosine kinase (SYK) inhibitor.

GSK143 is an orally active and highly selective spleen tyrosine kinase (SYK) inhibitor.

GSK143 is an Orally Active and Highly Selective Spleen Tyrosine Kinase SYK Inhibitor 2020 07 07 - GSK143 is an Orally Active and Highly Selective Spleen Tyrosine Kinase (SYK) Inhibitor

But, how does GSK143 work on the target? Let’s study it together. In the beginning, GSK143 is an orally active and highly selective spleen tyrosine kinase (SYK) inhibitor with a pIC50 of 7.5. Meanwhile, GSK143 inhibits phosphorylated Erk (pErk: pIC50=7.1). Nonetheless, GSK143 reduces inflammation and prevents the recruitment of immune cells in the intestinal muscularis in mice.

In the second place, GSK143 has an IC50 of 323 nM in CLL cells and abrogates early signaling events including SYK phosphorylation and calcium flux. Importantly, GSK143 reduces cytokine expression in bone marrow-derived macrophages in a concentration-dependent manner.

Last but not the least, GSK143 reduces inflammation and prevents the recruitment of immune cells in the intestinal muscularis of 1 mg/kg. Particularly, GSK143 reduces the cutaneous reverse passive Arthus reaction in a dose-dependent manner. It is by approximately 50% and 70% at 10 mg/kg and 30 mg/kg, respectively. By the way, GSK143 has a T1/2 of 4.2 hours, low clearance (16 mL/min/kg), moderate bioavailability of 30%, a Vss of 4.1 L/kg in rats.

All in all, GSK143 is an orally active and highly selective spleen tyrosine kinase (SYK) inhibitor.

References:

Abraham M Varghese, et al. Br J Haematol. 2018 Sep;182(6):927-930.

Sjoerd H W van Bree, et al. Gut. 2013 Nov;62(11):1581-90.

 

 

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