期刊
ACS OMEGA
卷 5, 期 1, 页码 822-831出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.9b03626
关键词
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资金
- Medical Research Council [ML/L007266/1, MC_UU_12022/1, MC_UU_12022/8]
- European Union
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- Cancer Research U.K.
- Wellcome Trust
- Higher Education Funding Council for England
- EPSRC [EP/F032773/1, EP/J017639/1]
- EPSRC [EP/J016012/1] Funding Source: UKRI
- MRC [MC_UU_12022/1, MR/L007266/1, MC_UU_12022/8] Funding Source: UKRI
Polo-like kinase 1 (PLK1) is a key regulator of mitosis and a recognized drug target for cancer therapy. Inhibiting the polo-box domain of PLK1 offers potential advantages of increased selectivity and subsequently reduced toxicity compared with targeting the kinase domain. However, many if not all existing polo-box domain inhibitors have been shown to be unsuitable for further development. In this paper, we describe a novel compound series, which inhibits the protein-protein interactions of PLK1 via the polo-box domain. We combine high throughput screening with molecular modeling and computer-aided design, synthetic chemistry, and cell biology to address some of the common problems with protein-protein interaction inhibitors, such as solubility and potency. We use molecular modeling to improve the solubility of a hit series with initially poor physicochemical properties, enabling biophysical and biochemical characterization. We isolate and characterize enantiomers to improve potency and demonstrate on-target activity in both cell-free and cell-based assays, entirely consistent with the proposed binding model. The resulting compound series represents a promising starting point for further progression along the drug discovery pipeline and a new tool compound to study kinase-independent PLK functions.
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