Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β‑Cell Proliferation

DYRK1A has been implicated as an
important drug target in various
therapeutic areas, including neurological disorders and oncology.
DYRK1A has more recently been shown to be involved in pathways regulating
human β-cell proliferation, thus making it a potential therapeutic
target for both Type 1 and Type 2 diabetes. Our group, using a high-throughput
phenotypic screen, identified harmine that is able to induce β-cell
proliferation both in vitro and in vivo. Since harmine has suboptimal kinase selectivity, we sought to expand
structure–activity relationships for harmine’s DYRK1A
activity, to enhance selectivity, while retaining human β-cell
proliferation capability. We carried out the optimization of the 1-position
of harmine and synthesized 15 harmine analogues. Six compounds showed
excellent DYRK1A inhibition with IC50 in the range of 49.5–264
nM. Two compounds, 2-2 and 2-8, exhibited
excellent human β-cell proliferation at doses of 3–30
μM, and compound 2-2 showed improved kinase selectivity
as compared to harmine.