DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

Abstract

The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes β-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small–molecule–induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.

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 ].…”

Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3β and DYRK1A Kinases: A Structural Perspective

“…The latter possess about equipotent DYRK1A and GSK3β inhibitory efficacy. This improvement of glucose homeostasis by the synergistic inhibition of DYRK1A and GSK3β hints at an opportunity for the curative therapy of diabetes. − …”

“…This improvement of glucose homeostasis by the synergistic inhibition of DYRK1A and GSK3β hints at an opportunity for the curative therapy of diabetes. 23 − 25 …”

Structural perspective on the design of selective DYRK1B inhibitors

“…DYRK1A gene is located at the Down Syndrome Critical Region (DSCR) of chromosome 21 and the kinase is widely considered a potential drug target in neurological disorders including Down Syndrome (DS), Alzheimer's disease and Parkinson's disease (Arranz et al, 2019;Courraud et al, 2021;van Bon et al, 2016). DYRK1A is also considered as a potential target in diabetes since it was shown that inhibition of DYRK1A induces β-cell proliferation (Ackeifi et al, 2020;Barzowska et al, 2021;Deboever et al, 2022). It is expected that targeting DYRK1A could increase β-cell numbers and restore endogenous insulin production.…”

“…The challenge lies in developing selective inhibitors that spare DYRK1A, thereby minimizing adverse effects and enhancing treatment efficacy (7). In the realm of regenerative medicine, both DYRK1A and DYRK1B are pivotal for human beta cell regeneration, with their inhibition showing promise in diabetes treatment by promoting beta cell proliferation (8,9). The DYRK1A gene is located at the Down Syndrome Critical Region (DSCR) of chromosome 21 and the kinase is widely considered a potential drug target in neurological disorders including Down Syndrome (DS), Alzheimer's, and Parkinson's disease (9)(10)(11)(12).…”