| Autor: |
Huggins, David J, Hardwick, Bryn S, Sharma, Pooja, Emery, Amy, Laraia, Luca, Zhang, Fengzhi, Narvaez, Ana J, Roberts-Thomson, Meredith, Crooks, Alex T, Boyle, Robert G, Boyce, Richard, Walker, David W, Mateu, Natalia, McKenzie, Grahame J, Spring, David R, Venkitaraman, Ashok R |
| Přispěvatelé: |
Huggins, David J [0000-0003-1579-2496], Apollo - University of Cambridge Repository, Huggins, David [0000-0003-1579-2496], Spring, David [0000-0001-7355-2824] |
| Rok vydání: |
2019 |
| Předmět: |
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| DOI: |
10.17863/cam.47063 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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