c-Jun N-terminal kinase inhibitors: a patent review (2010 – 2014)

Abstract

Introduction: c-Jun N-terminal kinases (JNKs) are involved in the emergence and progression of diverse pathologies such as neurodegenerative, cardiovascular and metabolic disorders as well as inflammation and cancer. In recent years, several highly selective pan-JNK inhibitors have been characterized and three chemical entities targeting JNKs have been investigated in clinical trials.

Areas covered: This review summarizes patents claiming inhibitors of all JNK isoforms published between 2010 and 2014. Although primarily focusing on the patent literature, relevant peer-reviewed publications related to the covered patents have also been included. Moreover, key patents claiming novel applications of previously published chemical entities are reviewed. The article highlights a total of 28 patents from nine pharmaceutical companies and academic research groups.

Expert opinion: Although some selective pan-JNK inhibitors with reasonable in vivo profiles are now available, little is known about the isoform selectivity required for each particular indication and the development of isoform-selective JNK inhibitors still represents a challenge in JNK drug discovery. Moreover, isoform-selective tool compounds are a prerequisite to a comprehensive understanding of the biology of each JNK isoform. Potential approaches towards such compounds include the design of type-II and type-I¹/₂ binders, which are absent in the current JNK inhibitor portfolios, as well as the design of novel allosteric inhibitors. Furthermore, covalent inhibition, which already led to the first high-quality probe for JNKs, might be further exploited for gaining selectivity and in vivo efficacy. With regard to a potential therapeutic application, the recently proposed concept of covalent reversible inhibitors is expected to be attractive.

Keywords:

• Alzheimer’s disease
• cancer
• cardiovascular disorders
• chemical probes
• c-Jun N-terminal kinase inhibitors
• dual leucine zipper kinase
• Huntington’s disease
• inflammation
• isoform selectivity
• JNK1
• JNK2
• JNK3
• metabolic disorders
• MAPK kinases
• mitogen-activated protein kinase kinase 4
• neurodegenerative disorders
• p38 MAP kinase
• Parkinson’s disease
• stroke

Acknowledgement

M Gehringer and F Muth have contributed equally to this work. The authors thank Francesco Ansideri for refining the manuscript.

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.

Notes

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