Novel selective thiadiazine DYRK1A inhibitor lead scaffold with human pancreatic β-cell proliferation activity.

Abstract The Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome, Alzheimer's disease), oncology, and diabetes (pancreatic β-cell expansion). Current small molecule DYRK1A inhibitors are ATP-competitive inhibitors that bind to the kinase in an active conformation. As a result, these inhibitors are promiscuous, resulting in pharmacological side effects that limit their therapeutic applications. None are in clinical trials at this time. In order to identify a new DYRK1A inhibitor scaffold, we constructed a homology model of DYRK1A in an inactive, DFG-out conformation. Virtual screening of 2.2 million lead-like compounds from the ZINC database, followed by in vitro testing of selected 68 compounds revealed 8 hits representing 5 different chemical classes. We chose to focus on one of the hits from the computational screen, thiadiazine 1 which was found to inhibit DYRK1A with IC 50 of 9.41 μM (K d = 7.3 μM). Optimization of the hit compound 1, using structure-activity relationship (SAR) analysis and in vitro testing led to the identification of potent thiadiazine analogs with significantly improved binding as compared to the initial hit (K d = 71–185 nM). Compound 3–5 induced human β-cell proliferation at 5 μM while showing selectivity for DYRK1A over DYRK1B and DYRK2 at 10 μM. This newly developed DYRK1A inhibitor scaffold with unique kinase selectivity profiles has potential to be further optimized as novel therapeutics for diabetes. Graphical abstract Image 1 Highlights • Homology model of DYRK1A in the inactive, DFG-out conformation was developed using DFGmodel protocol. • Virtual screen of the ZINC database and in vitro testing revealed hit thiadiazine 1 with DYRK1A K d = 7.3 µM. • Hit-to-lead SAR study was carried out by modifications at the 2-amino position to improve hit DYRK1A binding potency. • 27 analogues synthesized to identify two compounds with significantly improved binding to DYRK1A (K d = 71–185 nM). • New lead compound 3–5 induced human β-cell proliferation at 5 µM and improved selectivity for closely related kinases. [ABSTRACT FROM AUTHOR]