Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature

ABSTRACT

Introduction: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic serine-threonine protein kinase belonging to the CMGC group. DYRK1A hyperactivity appears to contribute to the development of a number of human malignancies and to cognitive deficits observed in Down syndrome and Alzheimer’s disease. As a result, the DYRK1A kinase represents an attractive target for the synthesis and optimization of pharmacological inhibitors of potential therapeutic interest.

Like most tyrosine kinase inhibitors developed up to the market, DYRK1A inhibitors are essentially acting by competing with ATP for binding at the catalytic site of the kinase.

Areas covered: This paper reviews patent activity associated with the discovery of synthetic novel heterocyclic molecules inhibiting the catalytic activity of DYRK1A.

Expert opinion: Despite the important role of DYRK1A in biological processes and the growing interest in the design of new therapeutic drugs, there are only few patented synthetic DYRK1A inhibitors and most of them were and are still developed by academic research groups, sometimes with industrial partners.

KEYWORDS:

• DYRK1A
• DYRK kinases
• heterocyclic compounds
• patents
• microwave chemistry
• kinase inhibitor
• down syndrome
• Alzheimer’s disease

Article highlights

• DYRK1A inhibitors have potential applications in various medical indications: Down syndrome, Alzheimer’s disease, several cancers, inflammation, diabetes.

• Numerous synthetic DYRK1A inhibitors have been described, some of which were inspired by natural alkaloids.

• Synthetic routes to heterocyclic inhibitors of DYRK1A are briefly presented.

• Most of the developed DYRK1A inhibitors are nitrogen-containing heterocycles.

• Academic research groups are very productive in this research area.

This box summarizes key points contained in the article.

Acknowledgments

TB and CF thank the University of Rouen, INSA Rouen (Engineers school of chemistry), CNRS and LABEX SynOrg (ANR-11-LABX-0029) for financial support. TLN is recipient of a CIFRE fellowship.

Declaration of interest

TB and CF are members of University of Rouen (FR) and declare no conflict of interest. TLN and YH are members of University of Strasbourg (FR) and declare no conflict of interest. LM is CEO and CSO of the ManRos Therapeutics start-up company and co-inventor on the Leucettines patent. 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 funded by University of Rouen, INSA Rouen (Engineers school of chemistry), CNRS and LABEX SynOrg (ANR-11-LABX-0029) and Fondation Jérôme Lejeune (LM) and Fonds Unique Interministériel (FUI TRIAD) (LM).