2. Academic Validation
  3. Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B

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

  • J Med Chem. 2024 Oct 10;67(19):17259-17289. doi: 10.1021/acs.jmedchem.4c01130.
Gerrit Wilms 1,  Kevin Schofield 2 3,  Shayna Maddern 3,  Christopher Foley 3,  Yeng Shaw 2,  Breland Smith 3,  L Emilia Basantes 3,  Katharina Schwandt 1,  Aaron Babendreyer 4,  Timothy Chavez 3,  Nicholas McKee 2,  Vijay Gokhale 5,  Sebastian Kallabis 6,  Felix Meissner 7,  Samantha N Rokey 3,  Travis Dunckley 8,  William R Montfort 3,  Walter Becker 1,  Christopher Hulme 2 3
Affiliations

Affiliations

  • 1 Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany.
  • 2 Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United States.
  • 3 Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States.
  • 4 Institute of Molecular Pharmacology, RWTH Aachen University, Aachen 52074, Germany.
  • 5 BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States.
  • 6 Core Facility Translational Proteomics, Institute of Innate Immunity, University Hospital Bonn, Bonn 53127, Germany.
  • 7 Department of Systems Immunology and Proteomics, Institute of Innate Immunity, University Hospital Bonn, Bonn 53127, Germany.
  • 8 ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, Arizona 85281, United States.
PMID: 39344427 DOI: 10.1021/acs.jmedchem.4c01130
Abstract

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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