Halekotte, Jakob, Witt, Lydia, Ianes, Chiara, Krueger, Marc, Buehrmann, Mike, Rauh, Daniel, Pichlo, Christian, Brunstein, Elena, Luxenburger, Andreas ORCID: 0000-0002-7574-8027, Baumann, Ulrich, Knippschild, Uwe, Bischof, Joachim and Peifer, Christian (2017). Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1 delta and Their Structural Relation to p38 alpha MAPK. Molecules, 22 (4). BASEL: MDPI AG. ISSN 1420-3049

Full text not available from this repository.

Abstract

The involvement of protein kinase CK1 delta in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1 delta inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38 alpha MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1 delta with compounds 11b (IC50 CK1 delta = 4 nM, IC50 CK1 epsilon = 25 nM), 12a (IC50 CK1 delta = 19 nM, IC50 CK1 epsilon = 227 nM), and 16b (IC50 CK1 delta = 8 nM, IC50 CK1 epsilon = 81 nM) being among the most potent CK1 delta-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 mu M) and Panc89 (EC50 = 1.5 mu M). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1 delta and 11b in p38 alpha.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Halekotte, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ianes, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buehrmann, MikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichlo, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunstein, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luxenburger, AndreasUNSPECIFIEDorcid.org/0000-0002-7574-8027UNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knippschild, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bischof, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-234514
DOI: 10.3390/molecules22040522
Journal or Publication Title: Molecules
Volume: 22
Number: 4
Date: 2017
Publisher: MDPI AG
Place of Publication: BASEL
ISSN: 1420-3049
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COLORECTAL-CANCER PATIENTS; MITOTIC SPINDLE FORMATION; CASEIN-KINASE; CELL-LINE; TETRASUBSTITUTED IMIDAZOLES; BIOLOGICAL EVALUATION; MAXIMUM-LIKELIHOOD; POTENT INHIBITORS; EXOCRINE PANCREAS; LIGAND COMPLEXESMultiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23451

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item