Discovery and\nFunctional Characterization of a Potent,\nSelective, and Metabolically Stable PROTAC of the Protein Kinases\nDYRK1A and DYRK1B

Small-molecule-induced protein degradation has emerged\nas a promising\npharmacological modality for inactivating disease-relevant protein\nkinases. DYRK1A and DYRK1B are closely related protein kinases that\nare involved in pathological processes such as neurodegeneration,\ncancer development, and adaptive immune homeostasis. Herein, we report\nthe development of the first DYRK1 proteolysis targeting chimeras\n(PROTACs) that combine a new ATP-competitive DYRK1 inhibitor with\nligands for the E3 ubiquitin ligase component cereblon (CRBN) to induce\nubiquitination and subsequent proteasomal degradation of DYRK1A and\nDYRK1B. The lead compound (DYR684) promoted fast, efficient, potent,\nand selective degradation of DYRK1A in cell-based assays. Interestingly,\nan enzymatically inactive splicing variant of DYRK1B (p65) resisted\ndegradation. Compared to competitive kinase inhibition, targeted degradation\nof DYRK1 by DYR684 provided improved suppression of downstream signaling.\nCollectively, our results identify DYRKs as viable targets for PROTAC-mediated\ndegradation and qualify DYR684 as a useful chemical probe for DYRK1A\nand DYRK1B.