Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015–2018)

ABSTRACT

Introduction: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors.

Areas covered: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years.

Expert opinion: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.

KEYWORDS:

• Small molecules
• selective Tyk2 inhibitors
• IFNα
• IL-12
• IL-23
• JAK-STAT

Article highlights

• Tyk2 associates with cytoplasmic tails of numerous cytokine receptors, induces intracellular signaling and modulates gene expression and transcription through STAT proteins.

• Tyk2 differs from other Jak family subtypes in its cytokine signaling specificity.

• Selective inhibition of Tyk2 results in the effective regulation of IFNα, IL12, and IL23, generating desirable pharmacological effects in both animal models and human clinical trials, while minimizing the potential side effects by other Jak family subtypes.

• Therapeutic opportunity for targeting selective inhibition of Tyk2 includes, but not limited to: skin related diseases such as psoriasis and systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis, cancer, and diabetes.

• In the past three years, the research activities on small molecule selective Tyk2 inhibitors have increased significantly compared to years before 2015, as reflected in increasing number of publication and patents.

This box summarizes key points contained in the article.

Declaration of interest

The author has 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.

Additional information

Funding

This work was supported by the National Science Foundation of China (Grant #. 81803417, 81730108), Key Project of Zhejiang Province Ministry of Science and Technology (Grant #. 2015C03055), Key Project of Hangzhou Ministry of Science and Technology（Grant #. 20162013A07, 20142013A63）.