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Isoquinolin‐1‐one Inhibitors of the MDM2–p53 Interaction
Author(s) -
Rothweiler Ulli,
Czarna Anna,
Krajewski Marcin,
Ciombor Jolanta,
Kalinski Cédric,
Khazak Vladimir,
Ross Günther,
Skobeleva Natalia,
Weber Lutz,
Holak Tad A.
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800025
Subject(s) - in silico , mdm2 , drug discovery , computational biology , protein–protein interaction , in vitro , chemistry , p53 protein , drug , gene , combinatorial chemistry , biochemistry , biology , pharmacology
p53 has been at the centre of attention for drug design since the discovery of its growth‐suppressive and pro‐apoptotic activity. Herein we report the design and characterisation of a new class of isoquinolinone inhibitors of the MDM2–p53 interaction. Our identification of druglike and selective inhibitors of this protein–protein interaction included a straightforward in silico compound‐selection process, a recently reported NMR spectroscopic approach for studying the MDM2–p53 interaction, and selectivity screening assays using cells with the same genetic background. The selected inhibitors were all able to induce apoptosis and the expression of p53‐related genes, but only the isoquinolin‐1‐one‐based inhibitors stabilised p53. Our NMR experiments give a persuading explanation for these results, showing that isoquinolin‐1‐one derivates are able to dissociate the preformed MDM2–p53 complex in vitro, releasing a folded and soluble p53. The joint application of these methods provides a framework for the discovery of protein interaction inhibitors as a promising starting point for further drug design.