JAK3 inhibitors for the treatment of inflammatory and autoimmune diseases: a patent review (2016–present)

ABSTRACT

Introduction

Up to now, a total of eight Janus kinase (JAK) inhibitors have been approved for the treatment of autoimmune and myeloproliferative disease. The JAK family belongs to the non-receptor tyrosine kinase family, consisting of JAK1, JAK2, JAK3, and Tyk2. Among these four subtypes, only JAK3 is mainly expressed in hematopoietic tissue cells and is exclusively associated with the cytokines shared in the common gamma-chain receptor subunit. Due to its specific tissue distribution and functional characteristics that distinguish it from the other JAKs family subtypes, JAK3 is a promising target for the treatment of autoimmune disease.

Areas covered

This study aimed to provide a comprehensive review of the available patent literature on JAK-family inhibitors published from 2016 to the present. In addition, an overview of the clinical activities of selective JAK3 inhibitors in recent years was provided.

Expert opinion

To date, no selective JAK3 inhibitors have been approved for use in clinics. Over the last 5 years, an increasing number of studies on JAK3 inhibitors, particularly ritlecitinib by Pfizer, have demonstrated their promising therapeutic potential. In this review, recent studies reported that selective JAK3 inhibitors may offer valid, interesting, and promising therapeutic potential in inflammatory and autoimmune diseases.

KEYWORDS:

• Janus kinase
• JAK3 subtype
• JAK3 inhibitor
• autoimmune disease
• patent review

Article Highlights

• JAK3 differs from other JAK family subtypes in its cytokine signaling specificity. In contrast to the ubiquitous expression of other JAKs, JAK3 is predominantly expressed in the hematopoietic system. In addition, JAK3 uniquely binds to only one cytokine receptor, the common gamma chain.

• In principle, restricted expression and function within the hematopoietic compartment of JAK3 should result in very limited side effects on other organs. Thus, selective inhibition of JAK3 should have a better risk-benefit ratio and higher efficacy in autoimmune disorders where lymphocyte differentiation is the driving factor.

• The design of compounds based on difference of the active site Cys909 residues between JAK3 and other JAK subtypes should theoretically lead to JAK3 inhibitors that are more selective than other JAK subtypes.

• Therapeutic opportunities for targeting selective inhibition of JAK3 include, but are not limited to rheumatoid arthritis, inflammatory bowel disease, cancer, diabetes as well as skin-related diseases such as alopecia areata, psoriasis, and systemic lupus erythematosus.

• Given that the JAK3 subtype is only responsible for the function of γc-associated cytokines, selective JAK3 inhibitor has the potential to overcome clinically occurring side effects by pan-JAKs inhibitors, such as severe infection, thrombosis and anemia.

Declaration of interests

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.

Reviewer disclosures

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

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81973338, 82104189).