Development of Bifunctional Inhibitors of Polo‐Like Kinase 1 with Low‐Nanomolar Activities Against the Polo‐Box Domain. (4th December 2015)

• Record Type: Journal Article
• Authors: Scharow, Andrej; Knappe, Daniel; Reindl, Wolfgang; Hoffmann, Ralf; Berg, Thorsten
• Is Part Of: Chembiochem. Volume 17:Number 8(2016)
• Page Start: 759
• Page End: 767
• Publication Date: 2015-12-04
• Subjects: bioorganic chemistry -- inhibitors -- peptides -- protein kinases -- protein–protein interactions; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500535
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Polo‐like kinase 1 (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 BI 2536, 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. Abstract : Take two : A design strategy for the development of polo‐like kinase 1 (Plk1) inhibitors incorporating both an inhibitor of the enzymatic domain and an inhibitor of the polo‐box domain (PBD) is reported. The most potent inhibitor displays low‐nanomolar activity against the Plk1 PBD and excellent selectivity over the PBDs of Plk2 and Plk3.