INTRODUCTIONAutoimmune diseases (ADs) are disorders induced by multiple inflammatory mediators, in which immune system attacks healthy tissues and triggers tissue injury. Targeted regulation of the activity of kinases that influence inflammation is one of the major therapies for ADs. Recently, investigational spleen tyrosine kinase (SYK) inhibitors have shown encouraging results in the AD therapy.AREAS COVEREDThis article provides a background on autoimmune diseases and provides an update on investigational SYK inhibitors. This literature review was conducted by searching publications about investigational SYK inhibitors in the treatment of ADs from experimental to clinical studies. The search terms used were SYK inhibitors, R406, fostamatinib (R788), P505-15 (PRT062607), entospletinib (GS-9973), R112, lanraplenib (GS-9876), cerdulatinib, R343, BAY-61-3606, GSK compound 143 (GSK143), R211, SKI-G-618, SKI-O-85, ER-27319, YM193306, RO9021 in conjunction with autoimmune disease using electronic databases including PubMed, EMBASE, MEDLINE and Google Scholar.EXPERT OPINIONSYK inhibitors are promising drugs with unique advantages and acceptable tolerability and safety for the treatment of ADs. However, the difficulties in developing highly selective SYK inhibitors and the unknown effects are challenges. Long-term and real-world data are essential to determine the risk-benefit ratio and true role of SYK inhibitors in the therapy of ADs.

01 Sep 2018·British Journal of Haematology

Highly selective SYK inhibitor, GSK143, abrogates survival signals in chronic lymphocytic leukaemia

Letter

Author: Newton, Darren ; Varghese, Abraham M. ; Munir, Talha ; Dickson, Marion ; Hillmen, Peter ; Tooze, Reuben M. ; Rawstron, Andy ; Doody, Gina M.

01 Nov 2013·GutQ1 · MEDICINE

Inhibition of spleen tyrosine kinase as treatment of postoperative ileus

Q1 · MEDICINE

Article

Author: Giovanna Farro ; Michael J Skynner ; Pedro Julian Gomez-Pinilla ; Guy E E Boeckxstaens ; Cesar Ramirez-Molina ; Cathy Cailotto ; Gianluca Matteoli ; Wouter J de Jonge ; Dave Lugo ; Kevin Lee ; Fleur Suzanne van de Bovenkamp ; Sjoerd H W van Bree ; Martina Di Giovangiulio ; Andrea Nemethova

OBJECTIVEIntestinal inflammation resulting from manipulation-induced mast cell activation is a crucial mechanism in the pathophysiology of postoperative ileus (POI). Recently it has been shown that spleen tyrosine kinase (Syk) is involved in mast cell degranulation. Therefore, we have evaluated the effect of the Syk-inhibitor GSK compound 143 (GSK143) as potential treatment to shorten POI.DESIGNIn vivo: in a mouse model of POI, the effect of the Syk inhibitor (GSK143) was evaluated on gastrointestinal transit, muscular inflammation and cytokine production. In vitro: the effect of GSK143 and doxantrazole were evaluated on cultured peritoneal mast cells (PMCs) and bone marrow derived macrophages.RESULTSIn vivo: intestinal manipulation resulted in a delay in gastrointestinal transit at t=24 h (Geometric Center (GC): 4.4 ± 0.3). Doxantrazole and GSK143 significantly increased gastrointestinal transit (GC doxantrazole (10 mg/kg): 7.2 ± 0.7; GSK143 (1 mg/kg): 7.6 ± 0.6), reduced inflammation and prevented recruitment of immune cells in the intestinal muscularis. In vitro: in PMCs, substance P (0-90 μM) and trinitrophenyl (0-4 μg/ml) induced a concentration-dependent release of β-hexosaminidase. Pretreatment with doxantrazole and GSK143 (0.03-10 μM) concentration dependently blocked substance P and trinitrophenyl induced β-hexosaminidase release. In addition, GSK143 was able to reduce cytokine expression in endotoxin-treated bone marrow derived macrophages in a concentration-dependent manner.CONCLUSIONSThe Syk inhibitor GSK143 reduces macrophage activation and mast cell degranulation in vitro. In addition, it inhibits manipulation-induced intestinal muscular inflammation and restores intestinal transit in mice. These findings suggest that Syk inhibition may be a new tool to shorten POI.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Lymphocytic Leukemia	Preclinical	GB	GSK Plc	02 Aug 2017
Postoperative ileus	Preclinical	GB	GSK Plc	13 Dec 2012
Autoimmune Diseases	Preclinical	GB	GSK Plc	09 Nov 2012

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