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  Development of Bifunctional Inhibitors of Polo-Like Kinase1 with Low-Nanomolar Activities Against the Polo-Box Domain

Scharow, A., Knappe, D., Reindl, W., Hoffmann, R., & Berg, T. (2016). Development of Bifunctional Inhibitors of Polo-Like Kinase1 with Low-Nanomolar Activities Against the Polo-Box Domain. CHEMBIOCHEM, 17(8, Special Issue: Protein–Protein Interactions), 759-767. doi:10.1002/cbic.201500535.

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 Creators:
Scharow, Andrej1, Author
Knappe, Daniel1, Author
Reindl, Wolfgang2, Author           
Hoffmann, Ralf1, Author
Berg, Thorsten1, Author
Affiliations:
1external, ou_persistent22              
2Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565172              

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Free keywords: FLUORESCENCE POLARIZATION; PLK1; CELLS; POLO-LIKE-KINASE-1; PHOSPHOPEPTIDES; ASSAY; IDENTIFICATION; RECOGNITION; ALKYLATION; REVEALSbioorganic chemistry; inhibitors; peptides; protein kinases; protein-protein interactions;
 Abstract: Polo-like kinase1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000375124500016
DOI: 10.1002/cbic.201500535
 Degree: -

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Title: CHEMBIOCHEM
Source Genre: Journal
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Publ. Info: POSTFACH 101161, 69451 WEINHEIM, GERMANY : WILEY-V C H VERLAG GMBH
Pages: - Volume / Issue: 17 (8, Special Issue: Protein–Protein Interactions) Sequence Number: - Start / End Page: 759 - 767 Identifier: ISSN: 1439-4227