Premium
Development of Bifunctional Inhibitors of Polo‐Like Kinase 1 with Low‐Nanomolar Activities Against the Polo‐Box Domain
Author(s) -
Scharow Andrej,
Knappe Daniel,
Reindl Wolfgang,
Hoffmann Ralf,
Berg Thorsten
Publication year - 2016
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500535
Subject(s) - polo like kinase , bifunctional , kinase , chemistry , phosphofructokinase 2 , biochemistry , enzyme , cell cycle , catalysis , cell
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.