TY  - JOUR
A1  - Walter, Anne
A1  - Chaikuad, Apirat
A1  - Helmer, Renate
A1  - Loaëc, Nadège
A1  - Preu, Lutz
A1  - Ott, Ingo
A1  - Knapp, Stefan
A1  - Meijer, Laurent
A1  - Kunick, Conrad
T1  - Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype
T2  - PLoS One
N2  - 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.
KW  - Chlorides
KW  - Crystal structure
KW  - Hydrogen bonding
KW  - Indoles
KW  - CNS melanoma
KW  - Kinase inhibitors
KW  - High performance liquid chromatography
KW  - Binding analysis
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46557
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-465577
SN  - 1932-6203
N1  - Copyright: © 2018 Walter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
VL  - 13
IS  - (5): e0196761
SP  - 1
EP  - 29
PB  - PLoS
CY  - Lawrence, Kan.
ER  -