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Rothweiler U , Czarna A , Krajewski M , Ciombor J , Kalinski C , Khazak V , Ross G , Skobeleva N , Weber L , Holak TA
Isoquinolin-1-one inhibitors of the MDM2-p53 interaction
Chemmedchem. 2008 Jul;3(7) :1118-1128
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Abstract
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-lone derivates are able to dissociate the preformed MDM2-p53 complex in vitro, releasing a folded and soluble p53. The joint application of these methods p!
Notes
ISI Document Delivery No.: 328TS Rothweiler, Ulli Czarna, Anna Krajewski, Marcin Ciombor, Jolanta Kalinski, Cedric Khazak, Vladimir Ross, Guenther Skobeleva, Natalia Weber, Lutz Holak, Tad A. WILEY-V C H VERLAG GMBH