A new and non-genotoxic approach to treating cancer is through small molecules that can specifically block the interaction between the transcription factor p53 and its negative regulator Mdm2. In their goal to identify better anticancer drugs with fewer side effects, Alexander Dömling and colleagues, University of Pittsburgh, USA, recently used software they developed to describe several new scaffolds that effectively disrupt the p53–Mdm2 interaction.
The software screens a very large chemical space of virtual multi-component reaction products, which can be instantaneously synthesized and undergo a reality check by physical screening. The team aimed to optimize potent Mdm2 antagonists by rapidly synthesizing all possible fluorine derivatives. Computational and biophysical studies, including a co-crystal structure determined by Holak’s group at the Max Planck Institute, Martinsried, Germany, were used to rationalize the small molecule–receptor interactions. Improved compounds from this project are currently undergoing preclinical development.
- Exhaustive Fluorine Scanning toward Potent p53–Mdm2 Antagonists
Y. Huang, S. Wolf, D. Koes, G. M. Popowicz, C. J. Camacho, T. A. Holak, A. Dömling,
ChemMedChem 2011, 7(01).