In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2

  title={In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2},
  author={Lyubomir T Vassilev and Binh Thanh Vu and Bradford J. Graves and Daisy M. Carvajal and Frank Podlaski and Zoran M Filipovic and Norman Kong and Ursula Kammlott and Christine M. Lukacs and Christian L Klein and Nader Fotouhi and Emily Aijun Burlingame Liu},
  pages={844 - 848}
MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2… 
Small-Molecule Antagonists of p53-MDM2 Binding: Research Tools and Potential Therapeutics
The first potent and selective low molecular weight inhibitors of MDM2-p53 binding, the Nutlins, are identified and their potent activity against osteosarcoma xenogrfts suggests thatMDM2 antagonists may have a clinical utility in the treatment of tumors with wild-type p53.
Small-molecule inhibitors of the p53-MDM2 interaction.
  • B. Vu, L. Vassilev
  • Biology, Chemistry
    Current topics in microbiology and immunology
  • 2011
In mice-bearing established human tumor xenografts, MDM2 antagonists caused tumor inhibition and regression at nontoxic concentrations, suggesting that they may have a therapeutic utility in the treatment of cancer.
Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.
RG7112 is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket ofMDM2, which stabilizes p53 and activates the p 53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.
Targeting the p53–MDM2 interaction to treat cancer
The first potent and selective small-molecule antagonists of MDM2, the Nutlins, have been identified and studies with Nutlins provided in vitro and in vivo proof-of-principle for targeting p53–MDM2 interaction for cancer therapy.
Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapeutics
Major advances have been made in the design of small-molecule inhibitors of the MDM2-p53 interaction in recent years, and several compounds have moved into advanced preclinical development or clinical trials.
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy.
This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies and highlight analogs of MI-219 and Nutlin-3.
Peptide activators of the p53 tumor suppressor.
This review aims to summarize the latest progress in the design of peptide activators of the p53 tumor suppressor with respect to several different classes of MDM2 and MDMX antagonists.
MDM2 inhibitors for cancer therapy.
  • L. Vassilev
  • Biology, Chemistry
    Trends in molecular medicine
  • 2007
Case Study: discovery of inhibitors of the MDM2-p53 protein-protein interaction.
The methods and techniques used in the discovery of small-molecule inhibitors of the MDM2-p53 interaction are described and a number of them have progressed into clinical trials for cancer treatment.


Inhibiting the p53–MDM2 interaction: an important target for cancer therapy
  • P. Chène
  • Biology, Medicine
    Nature Reviews Cancer
  • 2003
In this study, inhibiting the p53–MDM2 interaction with synthetic molecules should lead to p53-mediated cell-cycle arrest or apoptosis in p 53-positive stressed cells.
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
It is shown that, when expressed in Saccharomyces cerevisiae, human MDM2 inhibits human p53's ability to stimulate transcription by binding to a region that nearly coincides with the p53 acidic activation domain.
Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage.
The MDM2 oncogene encodes an inhibitor of the p53 tumor suppressor protein that regulates p53 in a negative feedback loop that enhances the activation of p53 by a DNA-damaging cancer chemotherapy agent in a synergistic fashion.
p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53
Results show that a peptide homologue of p53 is sufficient to induce p53 dependent cell death in cells overexpressing MDM2, and support the notion that disruption of the p53-MDM2 complex is a target for the development of therapeutic agents.
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-Residue transactivation domain peptide of p53 revealed that MDM 2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic α helix, supporting the hypothesis thatMDM2 inactivates p53 by concealing its transactivationdomain.
A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines.
It is reported here that an octamer synthetic peptide derived from p53 inhibits the p53-hdm2 interaction in vitro, and shows that inhibitors of the p 53-hdM2 interaction are very attractive candidates for the activation of thep53 pathway in tumours expressing wild-type p53.
The p53-Mdm2 module and the ubiquitin system.
Regulation of p53 stability
It is now becoming clear that the Mdm2 protein is central to the regulation of p53 stability and multiple pathways exist through which the activity of MDM2 can be inhibited.