Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Abstract

Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition—through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term “diabetic kinome” as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification ofDYRK1A

“…23,[70][71][72] Further diverse roles have been proposed for DYRK1A, including the phosphorylation of tau and amyloid proteins and in regulating pancreatic beta cell proliferation, leading to its investigation as a modulator of diseases ranging from Alzheimer's to diabetes. 71,[73][74][75] Consequently, several DYRK1A inhibitors have been developed which show ontarget efficacy and negligible toxicity in murine models and in a pilot human study, rendering it a key target for further development. [76][77][78] Inhibition of DYRK1A has also recently been reported to alter splicing and increase sensitivity to BCL2 inhibition in non-DYRK1A amplified AML.…”

DYRK1A inhibitors leucettines and TGF-β inhibitor additively stimulate insulin production in beta cells, organoids, and isolated mouse islets

“…Numerous pharmacological inhibitors against DYRK1A have been reported [15,17,[41][42][43][44][45][46]. Among these, we selected leucettines, which represent a group of well-characterized DYRK1A inhibitors derived from the leucettamine B (marine sponge alkaloid) (Fig 1) [24,[27][28][29][47][48][49][50][51][52].…”

The Omnipresence of DYRK1A in Human Diseases

“…However, numerous biological targets have been studied in this context, including DYRK1A. Studies show that DYRK1A small molecule inhibitors induce human β-cell proliferation both in vitro and in vivo [ 54 , 78 , 114 , 115 , 116 , 117 , 118 ]. Several studies have demonstrated that DYRK1A overexpression attenuated β-cell proliferation through NFAT dysregulation, a transcription factor that transactivates cell cycle-activating genes and represses cell cycle inhibitor genes including other CMGC, cyclins and p57 ( Table 1 ) [ 30 , 68 , 114 , 115 ].…”