Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2

ABSTRACT

Introduction: Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera.

Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013–2015 inclusive, and covers 95 patents from 42 applicants, split over two parts. The authors have ordered recent patents according to the primary applicant’s name, with part 2 covering J through Z.

Expert opinion: Inhibition of JAK-family kinases is an area of growing interest, catalysed by the maturity of data on marketed inhibitors ruxolitinib and tofacitinib in late stage clinical trials. Many applicants are pursuing traditional fast-follower strategies around these inhibitors, with a range of chemical strategies adopted. The challenge will be to show sufficient differentiation to the originator compounds, since dose limiting toxicities with such agents appear to be on target and mechanism-related and also considering that such agents may be available as generic compounds by the time follower agents reach market.

KEYWORDS:

• JAK
• JAK1 inhibitor
• JAK2 inhibitor
• JAK3 inhibitor
• TYK2 inhibitor
• Janus kinase inhibitors
• oncology
• rheumatoid arthritis
• myelofibrosis
• ruxolitinib
• tofacitinib

Article highlights

• There has been a surge in patent applications covering inhibitors of the JAK family enzymes following the approval of ruxolitinib and tofacitinib for the treatment of myelofibrosis and rheumatoid arthritis respectively

• Many companies are seeking to capitalise on these discoveries with a proliferation of applications of ‘fast-follower’ or ‘me-too’ agents

• The growth in applications covering selective agents within this important kinase sub-family is recognition of the therapeutic index limitations of existing therapies although data on how such selective agents perform in a clinical setting is limited at present.

• Selective inhibitors of JAK1 appear to offer potential to deliver a greater therapeutic index than existing pan-JAK inhibitors, with many reported agents representing further elaboration of previously disclosed scaffolds

• Selective inhibitors of JAK3 are increasingly disclosed and all appear to adopt a strategy of targeting an active site cysteine residue that, whilst unique to JAK3 in this family, is also present in a number of other kinases

• Selective inhibitors of TYK2 are emerging but reports are relatively scarce – this may reflect the challenges in gaining selectivity for this kinase over other JAK-family members, or may reflect the less mature understanding of the contribution of this kinase to disease progression.

This box summarizes key points contained in the article.

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.

Additional information

Funding

This paper was not funded.