890-P: Ultraselective DYRK1A/B Inhibitors Mediated ß-Cell Proliferation and Insulin Production In Vitro and In Vivo

Introduction and Objective: Non-selective DYRK1A/B inhibitors have been reported to stimulate pancreatic β-cell proliferation and insulin production. However off-target kinase inhibition remains a concern. Development of 2 novel highly selective DYRK1A/B inhibitors and results of in vitro and in vivo studies showing their ability to stimulate β-cell proliferation, mediate production of insulin and lowering of HbA1c levels in vivo are reported.

Methods: SM15238 and SM15268 (DMSO and harmine as -ve & +ve controls) were investigated in the 3D InSight™ Human Islet Microtissue (spheroids) system to assess β-cell proliferation and function. In vivo studies were conducted in 5-week-old male db/db mice receiving daily oral dosing (35 days) of either molecule or vehicle for 5 weeks (n=8/group), measuring body weight (BW), fasted and non-fasted glucose (GLU), HbA1c levels, OGTT, CMP18, and histological analysis of pancreatic tissue.

Results: Spheroids treated for 4 days with SM15238 and SM15268 (1 or 5μM) demonstrated increased β-cell proliferation compared to DMSO, a significant increase in stimulated insulin secretion at 1μM SM15238 and a similar trend at both concentrations of SM15268 (Dunnett’s 1-way ANOVA) compared to controls. Oral dosing of both molecules at 45 mg/kg once daily in db/db mice resulted in sustained increased circulating 4-hr fasted insulin levels. Mice treated with SM15268 had significantly reduced non-fasted and 4-hr fasted GLU levels and those treated with SM15238 significantly reduced GLU during OGTT. Dosing with both molecules resulted in decreases in HbA1c levels after 21 days. Histological analysis showed β-cell proliferation but no significant increase in α-cells.

Conclusions: In this early proof of concept study, selective small molecule inhibitors of DYRK1A/B mediated β-cell proliferation and induced positive changes in in vitro and in vivo hyperglycemic settings. Further toxicology and dose optimization studies are planned.