Development of E3-substrate (MDM2-p53)-binding inhibitors: structural aspects.
Inhibition of E3 ligase-substrate binding is the most direct approach for blocking protein ubiquitylation and degradation. However, protein-protein interactions have proven to be difficult targets for discovery of small molecules that bind at the interface and modulate protein activity in a selective manner. Recently, we developed the first potent and selective small-molecule inhibitors of the binding between MDM2 E3 ligase and its substrate p53 (Vassilev et al., 2004). This process was aided significantly by the acquisition and use of structural information. We describe herein how such information was obtained and used at various stages in the program. These applications included assessment of MDM2 as a target, evaluation of hits from high-throughput screening and the selection of lead molecules, and analysis of binding strategies used by the inhibitors as a basis for guiding studies of similar systems. These tools are likely to be useful in any attempt to find and develop druglike compounds that modulate the function of a protein-protein interaction.
Fry
David C
DC
Structural Chemistry Group, Hoffmann-La Roche, Inc., Nutley, New Jersey, USA.
Graves
Bradford
B
Vassilev
Lyubomir T
LT
D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2