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Searching for Dual Inhibitors of the MDM 2‐p53 and MDMX ‐p53 Protein–Protein Interaction by a Scaffold‐Hopping Approach
Author(s) -
Zaytsev Andrey,
Dodd Barry,
Magnani Matteo,
Ghiron Chiara,
Golding Bernard T.,
Griffin Roger J.,
Liu Junfeng,
Lu Xiaohong,
Micco Iolanda,
Newell David R.,
Padova Alessandro,
Robertson Graeme,
Lunec John,
Hardcastle Ian R.
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12474
Subject(s) - mdmx , chemistry , p53 protein , scaffold , scaffold protein , protein–protein interaction , biochemistry , computer science , suppressor , signal transduction , database , gene
Two libraries of substituted benzimidazoles were designed using a ‘scaffold‐hopping’ approach based on reported MDM 2‐p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM 2 X ‐ray structure. Benzimidazole libraries were prepared using an efficient solution‐phase approach and screened for inhibition of the MDM 2‐p53 and MDM X‐p53 protein–protein interactions. Key examples showed inhibitory activity against both targets.