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Searching for Dual Inhibitors of the MDM2‐p53 and MDMX‐p53 Protein–Protein Interaction by a Scaffold‐Hopping Approach |
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| Authors: | Andrey Zaytsev Barry Dodd Matteo Magnani Chiara Ghiron Bernard T. Golding Roger J. Griffin Junfeng Liu Xiaohong Lu Iolanda Micco David R. Newell Alessandro Padova Graeme Robertson John Lunec Ian R. Hardcastle |
| Affiliation: | 1. Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Newcastle University, Newcastle upon Tyne, UK;2. Siena Biotech S.p.A., Siena, Italy;3. Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, UK |
| Abstract: | Two libraries of substituted benzimidazoles were designed using a ‘scaffold‐hopping’ approach based on reported MDM2‐p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X‐ray structure. Benzimidazole libraries were prepared using an efficient solution‐phase approach and screened for inhibition of the MDM2‐p53 and MDMX‐p53 protein–protein interactions. Key examples showed inhibitory activity against both targets. |
| Keywords: | drug design drug discovery protein– protein interaction structure‐based drug design virtual screening |