Targeting MDM2 by the small molecule RITA: towards the development of new multi-target drugs against cancer.
BACKGROUND
The use of low-molecular-weight, non-peptidic molecules that disrupt the interaction between the p53 tumor suppressor and its negative regulator MDM2 has provided a promising alternative for the treatment of different types of cancer. Among these compounds, RITA (reactivation of p53 and induction of tumor cell apoptosis) has been shown to be effective in the selective induction of apoptosis, and this effect is due to its binding to the p53 tumor suppressor. Since biological systems are highly dynamic and MDM2 may bind to different regions of p53, new alternatives should be explored. On this basis, the computational "blind docking" approach was employed in this study to see whether RITA would bind to MDM2.


RESULTS
It was observed that RITA binds to the MDM2 p53 transactivation domain-binding cleft. Thus, RITA can be used as a lead compound for designing improved "multi-target" drugs. This novel strategy could provide enormous benefits to enable effective anti-cancer strategies.


CONCLUSIONS
This study has demonstrated that a single molecule can target at least two different proteins related to the same disease.
Espinoza-Fonseca
L Michel
LM
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. mef@ddt.biochem.umn.edu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy*; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D005663:Furans; D008024:Ligands; C118989:NSC 652287; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2