8T2H

DYRK1A complex with DYR530

8T2H の概要

• エントリーDOI: 10.2210/pdb8t2h/pdb
• 分子名称: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, (4P)-4-{(3M)-3-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl}pyridin-2-amine, TETRAETHYLENE GLYCOL, ... (5 entities in total)
• 機能のキーワード: kinase, inhibitor, alzheimer's disease, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86183.04

構造登録者

Montfort, W.R.,Basantes, L.E. (登録日: 2023-06-06, 公開日: 2024-05-15, 最終更新日: 2024-11-27)

主引用文献

Wilms, G.,Schofield, K.,Maddern, S.,Foley, C.,Shaw, Y.,Smith, B.,Basantes, L.E.,Schwandt, K.,Babendreyer, A.,Chavez, T.,McKee, N.,Gokhale, V.,Kallabis, S.,Meissner, F.,Rokey, S.N.,Dunckley, T.,Montfort, W.R.,Becker, W.,Hulme, C.
Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B.
J.Med.Chem., 67:17259-17289, 2024

PubMed 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.

PubMed: 39344427
DOI: 10.1021/acs.jmedchem.4c01130

実験手法

X-RAY DIFFRACTION (1.85 Å)