Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015)

ABSTRACT

Introduction: IRAK4 is located proximal to TLR/IL-1 receptors, and in preclinical studies, inhibits downstream signaling from these receptors. The development of novel small molecule inhibitors of this kinase has the potential to lead to new therapeutics to treat diseases such as rheumatoid arthritis, lupus, and lymphomas.

Areas covered: The aim of this review is to summarize the recent patent literature (2012–2015) surrounding small molecule inhibitors of IRAK4. Specific examples of the chemical matter from each patent will be discussed, including any data that are presented for the examples highlighted.

Expert opinion: There are currently many examples of highly potent and kinase selective IRAK4 inhibitors and some have been tested in various in vivo disease models, demonstrating robust pre-clinical efficacy. Several compounds appear to have the ‘drug-like’ properties to advance to the clinic, with Pfizer having already initiated several phase I studies.

KEYWORDS:

• IRAK4
• inflammation
• TLR signaling
• IL-R signaling
• serine-threonine kinase inhibitor
• PF-06650833

Article highlights

• IRAK4 is involved in MyD88 signaling cascades and is hypothesized to play a role in inflammation related disorders as well as in oncology.

• Many IRAK4 inhibitors appear to have dual IRAK4/IRAK1 inhibition due to a high sequence homology between the two kinases, however it is not clear as to the biological relevance of selective IRAK4 versus dual inhibitors.

• The development of IRAK4 kinase inhibitors has accelerated over the past few years with multiple companies now reporting very potent inhibitors that are active in cellular, whole blood and animal models of disease.

• Although several IRAK4 inhibitors appear poised to enter human trials, only one is currently in the clinic: PF-06650833 which has multiple ongoing phase I trials.

This box summarizes key points contained in the article.

Declaration of interest

WM Seganish is an employee of Merck Sharp and Dohme Corp. 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.