Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases

ABSTRACT

Introduction

Autoimmune 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 covered

This 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 opinion

SYK 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.

KEYWORDS:

• Spleen tyrosine kinase
• autoimmune diseases
• SYK inhibitors
• R406
• fostamatinib

Article highlights

• Agents used to treat autoimmune diseases (ADs) include glucocorticoid, disease-modifying antirheumatic drugs (DMARDs), biological agents (such as TNF-α inhibitors, IL-6 inhibitors, etc.) and tyrosine kinase inhibitors (TKIs).

• Because of the key role of spleen tyrosine kinase (SYK) in immunity, numerous SYK inhibitors have been investigated and have yielded promising results in ADs.

• Fostamatinib was the first oral SYK inhibitor developed for the treatment of rheumatoid arthritis and lymphoid malignancies.

• P505-15 could safely, effectively, and selectively inhibit human SYK kinase function after once daily oral administration.

• R343 blocks allergic reactions to allergens in asthmatic patients; it is well tolerated and has potential benefits in the short- and long-term treatment of asthma.

• R112 is an ATP-competitive SYK inhibitor that is effective in inhibiting IgE-triggered mast cell activities in allergic disorders.

• RO9021 is a new orally ATP-competitive inhibitor of SYK that inhibits multiple immune-signaling pathways in diverse cell types and participates in bone metabolism.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Conflict of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part by the grants from the National Natural Science Foundation of China (82102595, 81974342) and China Postdoctoral Science Foundation (2021TQ0143).