Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B

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