6FT9

Crystal structure of CLK1 in complex with inhibitor 16

Summary for 6FT9

• Entry DOI: 10.2210/pdb6ft9/pdb
• Descriptor: Dual specificity protein kinase CLK1, 2-bromanyl-3-phenyl-1~{H}-pyrrolo[3,4-g]indol-8-one, BROMIDE ION, ... (7 entities in total)
• Functional Keywords: kinase, inhibitor, splicing kinase, clk, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: P49759
• Total number of polymer chains: 3
• Total formula weight: 120774.08

Authors

Chaikuad, A.,Walter, A.,von Delft, F.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Kunick, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2018-02-20, release date: 2018-05-16, Last modification date: 2024-01-17)

Primary citation

Walter, A.,Chaikuad, A.,Helmer, R.,Loaec, N.,Preu, L.,Ott, I.,Knapp, S.,Meijer, L.,Kunick, C.
Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype.
PLoS ONE, 13:e0196761-e0196761, 2018

PubMed Abstract: Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.

PubMed: 29723265
DOI: 10.1371/journal.pone.0196761

Experimental method

X-RAY DIFFRACTION (1.87 Å)