The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

Abstract

DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.

Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function

“…While Mdivi-1, Dynasore, and P110 suppress tumor malignancy, direct inhibition of mitochondrial fission may be toxic to life. DYRK3 may be an upstream regulator of DRP1 and may be a target of chemical inhibitors such as Harmine and GSK-626616, which were proposed as novel and promising cancer treatment strategies [ 48 , 49 ]. Harmine in particular has been used in clinical studies and can penetrate the blood brain barrier, allowing for brain-specific delivery [ 50 ].…”

Loss of the DYRK1A protein kinase results in reduction of ribosomal protein genes expression, ribosome mass and translation defects

“…The M4 motif matches the palindromic sequence that is bound by the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) protein kinase (Di Vona et al 2015). DYRK1A fulfills many diverse functions by phosphorylating a wide range of substrates (Arbones et al 2019;Boni et al 2020) and it is a kinase with exquisite gene dosage dependency. On the one hand, DYRK1A overexpression in individuals with trisomy 21 has been associated to several of the pathological symptoms associated with Down syndrome (DS) (Stringer et al 2017).…”

“…On the other hand, de novo mutations in one DYRK1A allele cause a rare clinical syndrome known as DYRK1A haploinsufficiency syndrome (OMIM#614104) (van Bon et al 2016;Arranz et al 2019; and references therein). DYRK1A has also been proposed as a pharmacological target for neurodegenerative disorders, diabetes and cancer (Branca et al Luna et al 2019;Boni et al 2020;Scavuzzo and Borowiak 2020). We have shown that DYRK1A is a transcriptional activator when recruited to proximal promoter regions of a subset of genes that are enriched for the palindromic motif TCTCGCGAGA (Di Vona et al 2015).…”

How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine

“…The DYRK1A gene is localized on human chromosome 21, and substantial evidence supports the hypothesis that DYRK1A overexpression significantly contributes to the altered brain development and intellectual disability in individuals with Down syndrome [ 3 ]. Furthermore, DYRK1A has been implicated in neurodegenerative processes [ 4 ], certain cancers [ 5 ] and regulation of pancreatic β-cell proliferation, suggesting inhibition of DYRK1A as a novel therapeutic strategy in diabetes [ 6 , 7 ]. Thus, inhibitors of DYRK1A are of interest not only as chemical probes for the functional characterization of DYRK1A’s role in these pathological processes but also as potential therapeutics.…”