The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regula- tors, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53- MDM2 interaction, and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.

Lauria, A., Tutone, M., Ippolito, M., Pantano, L., & Almerico, A.M. (2010). Molecular Modeling Approaches in the Discovery of New Drugs for Anti-Cancer Therapy: The Investigation of p53-MDM2 Interaction and its Inhibition by Small Molecules. CURRENT MEDICINAL CHEMISTRY, 2010(17), 3142-3154.

Molecular Modeling Approaches in the Discovery of New Drugs for Anti-Cancer Therapy: The Investigation of p53-MDM2 Interaction and its Inhibition by Small Molecules

LAURIA, Antonino;TUTONE, Marco;PANTANO, Licia;ALMERICO, Anna Maria
2010

Abstract

The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regula- tors, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53- MDM2 interaction, and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.
Settore CHIM/08 - Chimica Farmaceutica
Lauria, A., Tutone, M., Ippolito, M., Pantano, L., & Almerico, A.M. (2010). Molecular Modeling Approaches in the Discovery of New Drugs for Anti-Cancer Therapy: The Investigation of p53-MDM2 Interaction and its Inhibition by Small Molecules. CURRENT MEDICINAL CHEMISTRY, 2010(17), 3142-3154.
File in questo prodotto:
File Dimensione Formato  
10CMC3442.PDF

non disponibili

Descrizione: pdf
Dimensione 7.79 MB
Formato Adobe PDF
7.79 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/51317
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 42
  • ???jsp.display-item.citation.isi??? 42
social impact