Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β‑Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor

Recently, our group identified that
harmine is able to induce β-cell
proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT
pathway. Since, harmine suffers from a lack of selectivity, both against
other kinases and CNS off-targets, we therefore sought to expand structure–activity
relationships for harmine’s DYRK1A activity, to enhance selectivity
for off-targets while retaining human β-cell proliferation activity.
We carried out optimization of the 9-N-position of
harmine to synthesize 29 harmine-based analogs. Several novel inhibitors
showed excellent DYRK1A inhibition and human β-cell proliferation
capability. An optimized DYRK1A inhibitor, 2-2c, was
identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets,
as well as in vivo efficacy for β-cell proliferation and regeneration
at lower doses than harmine. Collectively, these findings demonstrate
that 2-2c is a much improved in vivo lead candidate as
compared to harmine for the treatment of diabetes.