Discovery of DYR684, a First-in-Class DYRK1A/B PROTAC

Abstract

Alternative to enzyme inhibition, 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. Here we report the development of 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 overexpressed and endogenous DYRK1A in cell-based assays. Although DYR684 was also active against DYRK1B, we observed that an enzymatically inactive splicing variant of DYRK1B (p65) was resistant to degradation. Compared to competitive kinase inhibition, targeted degradation of DYRK1 by DYR684 provided improved suppression of downstream signaling. Moreover, DYR684 sensitized SH-SY5Y neuroblastoma cells to the cytotoxic effects of the anticancer drug cisplatin. Collectively, our results identify DYRK1A and DYRK1B as viable targets for PROTAC-mediated degradation and qualify DYR684 as a suitable chemical probe for functional studies of the catalytically active DYRK1A and DYRK1B variants.