Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype

Walter, Anne GND; Chaikuad, Apirat; Helmer, Renate GND; Loa͏ëc, Nadège; Preu, Lutz GND; Ott, Ingo GND; Knapp, Stefan; Meijer, Laurent; Kunick, Conrad ORCID

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.


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Walter, Anne / Chaikuad, Apirat / Helmer, Renate / et al: Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype. Braunschweig 2018.

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