8P04
Crystal structure of human CLK1 in complex with Leucettinib-92
Summary for 8P04
| Entry DOI | 10.2210/pdb8p04/pdb |
| Descriptor | Dual specificity protein kinase CLK1, (4~{Z})-2-(1-adamantylamino)-4-(1,3-benzothiazol-6-ylmethylidene)-1~{H}-imidazol-5-one (3 entities in total) |
| Functional Keywords | kinase, typ1 inhibitor, clk1, leicettinib, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 39960.00 |
| Authors | Kraemer, A.,Schroeder, M.,Meijer, L.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2023-05-09, release date: 2023-05-17, Last modification date: 2023-11-22) |
| Primary citation | Deau, E.,Lindberg, M.F.,Miege, F.,Roche, D.,George, N.,George, P.,Kramer, A.,Knapp, S.,Meijer, L. Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B. J.Med.Chem., 66:10694-10714, 2023 Cited by PubMed Abstract: Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) recently attracted attention due to their central involvement in various pathologies. We here describe a family of DYRK/CLK inhibitors derived from Leucettines and the marine natural product Leucettamine B. Forty-five 2-functionalized 2-aminoimidazolin-4-ones bearing a fused [6 + 5]-heteroarylmethylene were synthesized. Benzothiazol-6-ylmethylene was selected as the most potent residue among 15 different heteroarylmethylenes. 186 2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene, collectively named Leucettinibs, were synthesized and extensively characterized. Subnanomolar IC (0.5-20 nM on DYRK1A) inhibitors were identified and one Leucettinib was modeled in DYRK1A and co-crystallized with CLK1 and the weaker inhibited off-target CSNK2A1. Kinase-inactive isomers of Leucettinibs (>3-10 μM on DYRK1A), named iso-Leucettinibs, were synthesized and characterized as suitable negative control compounds for functional experiments. Leucettinibs, but not iso-Leucettinibs, inhibit the phosphorylation of DYRK1A substrates in cells. Leucettinibs provide new research tools and potential leads for further optimization toward therapeutic drug candidates. PubMed: 37487467DOI: 10.1021/acs.jmedchem.3c00884 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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