TY - JOUR
T1 - Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B
AU - Wilms, Gerrit
AU - Schofield, Kevin
AU - Maddern, Shayna
AU - Foley, Christopher
AU - Shaw, Yeng
AU - Smith, Breland
AU - Basantes, L. Emilia
AU - Schwandt, Katharina
AU - Babendreyer, Aaron
AU - Chavez, Timothy
AU - McKee, Nicholas
AU - Gokhale, Vijay
AU - Kallabis, Sebastian
AU - Meissner, Felix
AU - Rokey, Samantha N.
AU - Dunckley, Travis
AU - Montfort, William R.
AU - Becker, Walter
AU - Hulme, Christopher
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/10/10
Y1 - 2024/10/10
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.4c01130
DO - 10.1021/acs.jmedchem.4c01130
M3 - Article
C2 - 39344427
AN - SCOPUS:85205798343
SN - 0022-2623
VL - 67
SP - 17259
EP - 17289
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -