7QRA

Crystal structure of CK1 delta in complex with VN725

7QRA の概要

• エントリーDOI: 10.2210/pdb7qra/pdb
• 分子名称: Casein kinase I isoform delta, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: kinase, ck1d, inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 140722.24

構造登録者

Chaikuad, A.,Nemec, V.,Paruch, K.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2022-01-10, 公開日: 2023-01-18, 最終更新日: 2024-02-07)

主引用文献

Nemec, V.,Khirsariya, P.,Janovska, P.,Moyano, P.M.,Maier, L.,Prochazkova, P.,Kebkova, P.,Gybel', T.,Berger, B.T.,Chaikuad, A.,Reinecke, M.,Kuster, B.,Knapp, S.,Bryja, V.,Paruch, K.
Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity.
Angew.Chem.Int.Ed.Engl., 62:e202217532-e202217532, 2023

PubMed Abstract: Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1α, δ and ϵ. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms. At proper concentrations, MU1250 and MU1500 allow for specific targeting of CK1δ or dual inhibition of CK1δ/ϵ in cells. The compound MU1742 also efficiently inhibits CK1α and, to our knowledge, represents the first potent and highly selective inhibitor of this enzyme. In addition, we demonstrate that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, e.g. p38α, as exemplified by the compound MU1299.

PubMed: 36625768
DOI: 10.1002/anie.202217532

実験手法

X-RAY DIFFRACTION (2.4 Å)