Selective Degradation of Polo-like Kinase 1 by a Hydrophobically Tagged Inhibitor of the Polo-Box Domain

被引:31
作者
Rubner, Stefan [1 ]
Scharow, Andrej [1 ]
Schubert, Sabine [1 ]
Berg, Thorsten [1 ]
机构
[1] Univ Leipzig, Inst Organ Chem, Johannisallee 29, D-04103 Leipzig, Germany
关键词
apoptosis; inhibitors; mitotic arrest; protein degradation; protein-protein interactions; E3 UBIQUITIN LIGASE; FLUORESCENCE POLARIZATION; PROTEIN-DEGRADATION; DRUG DISCOVERY; CANCER-CELLS; PLK1; POLO-LIKE-KINASE-1; BROMODOMAIN; VHL;
D O I
10.1002/anie.201809640
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Hydrophobic tagging (HT) of bioactive compounds can induce target degradation via the proteasomal pathway. The first application of hydrophobic tagging to an existing inhibitor of protein-protein interactions is now presented. We developed Poloxin-2HT by fusing an adamantyl tag to Poloxin-2, an inhibitor of the polo-box domain of the protein kinase Plk1, which is a target for tumor therapy. Poloxin-2HT selectively reduced the protein levels of Plk1 in HeLa cells and had a significantly stronger effect on cell viability and the induction of apoptosis than the untagged PBD inhibitor Poloxin-2. The change in cellular phenotype associated with the addition of the hydrophobic tag to Poloxin-2 demonstrated that Poloxin-2HT targets Plk1 in living cells. Our data validate hydrophobic tagging of selective inhibitors of protein-protein interactions as a novel strategy to target and destroy disease-relevant proteins.
引用
收藏
页码:17043 / 17047
页数:5
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