Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016-2018)

ABSTRACT

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is the most upstream kinase in Toll/Interleukin-1 receptor (TIR) signaling. Human and rodent genetics support the role of IRAK4 in immune function and the involvement of IRAK4-dependent signaling in certain cancers is hypothesized. The accumulating evidence has motivated the discovery of IRAK4 inhibitors that could be used therapeutically.

Areas covered: This review summarizes patents published in 2016–2018 claiming IRAK4 inhibitors. Representative analogues from each patent are presented with a focus on compounds that have been profiled in cellular and in vivo assays.

Expert opinion: The last three years have seen an increased number of IRAK4 inhibitors with which to assess the therapeutic potential of the target. At least 5 companies are believed to have advanced to the clinic. Pfizer is in phase II for rheumatoid arthritis (RA). The outcomes of these studies should inform on the therapeutic potential in autoimmune disease and cancer.

KEYWORDS:

• CA-4948
• inflammation
• interleukin-1 receptor-associated kinase
• Myd88
• PF-06650833
• rheumatoid arthritis
• Toll/IL-1R

Article highlights

• IRAK4 is the most proximal kinase in the Toll-like receptor (TLR)/IL-1R signaling cascade. Activation of the cascade triggers assembly of the myddosome complex and the downstream production of proinflammatory cytokines. Human and rodent genetics support the role of IRAK4 in the immune response.

• Over a dozen pharmaceutical companies have reported the discovery of IRAK4 inhibitors. Many of the reported compounds are potent enzyme inhibitors. IRAK4 inhibitors have been found to be active in a broad range of cellular and in vivo models.

• The work disclosed in patent applications over the last several years has led to multiple IRAK4 inhibitors being advanced to the clinic. Pfizer has enrolled patients in a phase II trial for RA.

• Emerging data suggests IRAK4 inhibition may offer a therapeutic benefit in the treatment of cancer. Aurigene and Curis have reported the start of a clinical trial evaluating IRAK4 inhibition for non-Hodgkin lymphoma.

• Opportunities remain to better understand the role of IRAK4 in myddosome signaling and in combination therapy for cancer. The compounds disclosed over the last several years should provide adequate tools to do so.

This box summarizes key points contained in the article.

Declaration of interest

WT McElroy is an employee of Merck Sharp and Dohme Corp., a subsidiary or Merck & Co., Inc., Kenilworth, NJ, USA (MSD). The author has no other 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 apart from those disclosed

Reviewer Disclosures

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

Additional information

Funding

This paper was not funded.