7QRB

Crystal structure of CK1 delta in complex with PK-09-129

Summary for 7QRB

• Entry DOI: 10.2210/pdb7qrb/pdb
• Descriptor: Casein kinase I isoform delta, SULFATE ION, 3-(dimethylamino)-~{N}-[4-[4-(4-fluorophenyl)-5-(1~{H}-pyrrolo[2,3-b]pyridin-4-yl)imidazol-1-yl]cyclohexyl]propane-1-sulfonamide, ... (4 entities in total)
• Functional Keywords: kinase, ck1d, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 140854.52

Authors

Chaikuad, A.,Khirsariya, P.,Paruch, K.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2022-01-10, release date: 2023-01-18, Last modification date: 2024-02-07)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)