Small-Molecule-Mediated Depletion of the Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1B (DYRK1B)...

Members of the DYRK kinase family have been implicated in the regulation of key metabolic processes. In particular, DYRK1B plays a central role in hepatic lipid metabolism and fatty liver disease. Notably, these functions depend not only on the enzyme's catalytic activity but also on scaffolding properties. Consequently, therapeutic ambitions aiming to target the entire spectrum of DYRK1B functions must inactivate or eliminate the protein itself rather than merely inhibiting its enzymatic activity, as is achieved by current kinase inhibitors. In this study, we describe a small molecule from the leucettinib class of DYRK inhibitors (LCTB-92) that not only suppresses DYRK kinase activity but also promotes selective ablation of the DYRK1B protein while sparing the closely related paralog DYRK1A. The identification of this compound establishes a foundation for the development of selective agents capable of targeting the entire DYRK1B protein scaffold, thereby addressing catalytic-dependent as well as catalytic-independent kinase functions.