Isoquinolin-1-one inhibitors of the MDM2-p53 interaction.
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.
Rothweiler
Ulli
U
Max Planck Institute for Biochemistry, 82152 Martinsried, Germany.
Czarna
Anna
A
Krajewski
Marcin
M
Ciombor
Jolanta
J
Kalinski
Cédric
C
Khazak
Vladimir
V
Ross
Günther
G
Skobeleva
Natalia
N
Weber
Lutz
L
Holak
Tad A
TA
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D017510:Protein Folding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2