6Q8P

Structure of CLK1 with bound N-methyl-10-nitropyrido[3,4-g]quinazolin-2-amine

Summary for 6Q8P

• Entry DOI: 10.2210/pdb6q8p/pdb
• Descriptor: Dual specificity protein kinase CLK1, ~{N}-methyl-10-nitro-pyrido[3,4-g]quinazolin-2-amine, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: transferase, serine/threonine-protein kinase, tyrosine-protein kinase, nucleus, inhibitor, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 119549.33

Authors

Joerger, A.C.,Chatterjee, D.,Schroeder, M.,Tazarki, H.,Zeinyeh, W.,Esvan, Y.J.,Khiari, J.,Josselin, B.,Baratte, B.,Bach, S.,Ruchaud, S.,Anizon, F.,Giraud, F.,Moreau, P.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2018-12-15, release date: 2019-02-20, Last modification date: 2024-01-24)

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

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: 30731399
DOI: 10.1016/j.ejmech.2019.01.052

Experimental method

X-RAY DIFFRACTION (3 Å)