Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1BClick to copy article linkArticle link copied!
- Gerrit WilmsGerrit WilmsInstitute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, GermanyMore by Gerrit Wilms
- Kevin SchofieldKevin SchofieldDivision of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United StatesDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Kevin Schofield
- Shayna MaddernShayna MaddernDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Shayna Maddern
- Christopher FoleyChristopher FoleyDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Christopher Foley
- Yeng ShawYeng ShawDivision of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United StatesMore by Yeng Shaw
- Breland SmithBreland SmithDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Breland Smith
- L. Emilia BasantesL. Emilia BasantesDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by L. Emilia Basantes
- Katharina SchwandtKatharina SchwandtInstitute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, GermanyMore by Katharina Schwandt
- Aaron BabendreyerAaron BabendreyerInstitute of Molecular Pharmacology, RWTH Aachen University, Aachen 52074, GermanyMore by Aaron Babendreyer
- Timothy ChavezTimothy ChavezDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Timothy Chavez
- Nicholas McKeeNicholas McKeeDivision of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United StatesMore by Nicholas McKee
- Vijay GokhaleVijay GokhaleBIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Vijay Gokhale
- Sebastian KallabisSebastian KallabisCore Facility Translational Proteomics, Institute of Innate Immunity, University Hospital Bonn, Bonn 53127, GermanyMore by Sebastian Kallabis
- Felix MeissnerFelix MeissnerDepartment of Systems Immunology and Proteomics, Institute of Innate Immunity, University Hospital Bonn, Bonn 53127, GermanyMore by Felix Meissner
- Samantha N. RokeySamantha N. RokeyDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Samantha N. Rokey
- Travis DunckleyTravis DunckleyASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, Arizona 85281, United StatesMore by Travis Dunckley
- William R. MontfortWilliam R. MontfortDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by William R. Montfort
- Walter Becker*Walter Becker*Email: [email protected]Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, GermanyMore by Walter Becker
- Christopher Hulme*Christopher Hulme*Email: [email protected]Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United StatesDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United StatesMore by Christopher Hulme
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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