Dual leucine zipper kinase (MAP3K12) modulators: a patent review (2010–2015)

ABSTRACT

Introduction: The dual leucine zipper kinase (DLK, MAP3K12) is essential for neuronal development and has been shown to mediate axon regeneration. On the other hand, DLK is involved in the pathogenesis of neurodegenerative disease and diabetes mellitus. Several patents have been published claiming to modulate or inhibit DLK by various approaches including ATP competitive inhibitors. In addition, two publications describe SAR of highly selective DLK inhibitors with efficacy in distinct mouse models of neurodegeneration.

Areas covered: This review summarized patents claiming to modulate DLK activity published between 2010 and 2015. Peer-reviewed publications related to the patents and additional peer-reviewed publications are included. This article describes 18 patents from three pharmaceutical companies and three academic research groups.

Expert opinion: Several methods are proposed to modulate DLK activity, some of them very experimental and not suitable for easy application in patients. ATP competitive kinase inhibitors exert high affinity, but for the majority, no information about their selectivity is available. To date, two inhibitors have been tested in mice. Given the controversial findings that DLK is required for neurodegeneration and for axon regeneration, more research is needed to further elucidate the regulation and the function of this kinase in diverse organs/tissues and under physiological and pathological conditions.

KEYWORDS:

• Axon regeneration
• diabetes mellitus type 2
• dual leucine zipper kinase
• mitogen-activated kinases
• mixed lineage kinase
• neurodegeneration

Article highlights

• Modulation of DLK activity is a suitable drug target.

• Experimental approaches to modulate DLK at different levels are proposed but their delivery remains a problem.

• Several type 1 ATP competitive DLK inhibitors with high potency were developed.

• Selectivity of the ATP competitive DLK inhibitors is not sufficiently addressed.

• ADME properties of the ATP competitive DLK inhibitors unclear for most inhibitors.

This box summarizes key points contained in the article.

Acknowledgement

The authors thank E. Schwedhelm for critically reading 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.