6Q8K
CLK1 with bound pyridoquinazoline
Summary for 6Q8K
| Entry DOI | 10.2210/pdb6q8k/pdb |
| Descriptor | Dual specificity protein kinase CLK1, 1,2-ETHANEDIOL, ~{N}2-(3-morpholin-4-ylpropyl)pyrido[3,4-g]quinazoline-2,10-diamine, ... (4 entities in total) |
| Functional Keywords | clk1, dual specifity protein kinase clk1, inhibitor, kinase, structural genomics, structural genomics consortium, sgc, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 39981.99 |
| Authors | Schroeder, M.,Tazarki, H.,Zeinyeh, W.,Esvan, Y.J.,Khiari, J.,Joesselin, B.,Bach, S.,Ruchaud, S.,Anizon, F.,Giraud, F.,Moreau, P.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2018-12-14, release date: 2019-02-20, Last modification date: 2024-05-15) |
| Primary citation | Tazarki, H.,Zeinyeh, W.,Esvan, Y.J.,Knapp, S.,Chatterjee, D.,Schroder, M.,Joerger, A.C.,Khiari, J.,Josselin, B.,Baratte, B.,Bach, S.,Ruchaud, S.,Anizon, F.,Giraud, F.,Moreau, P. New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis. Eur J Med Chem, 166:304-317, 2019 Cited by PubMed Abstract: Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design. PubMed: 30731399DOI: 10.1016/j.ejmech.2019.01.052 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.29 Å) |
Structure validation
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