Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer Therapy
By S. Shangary, Shaomeng Wang. Annual Review of Pharmacology and Toxicology, 2009
601 citations recorded by the source corpus.
Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 proteins are two alternative mechanisms for the inactivation of p53 function. Designing small molecules to block the MDM2-p53 interaction and reactivate the p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies. A number of these small-molecule inhibitors, such as analogs of MI-219 and Nutlin-3, have progressed to advanced preclinical development or early phase cinical trials.
Subfields: Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/65a85cdcc9448f7af289a636080f03783159f90d
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In Molecular Biology
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In Oncology
Citations in the corpus
- Systematic Analysis of Helical Protein Interfaces Reveals Targets for Synthetic Inhibitors (2010, background): “(7) The complex between transcription factor p53 and its regulator HDM2 is inhibited by nutlins (Figure 1, panel c),(8,9) and there are highly potent small molecule antagonists, including ABT-737 and A-385358, of the interactions between Bcl-xL and BH3 domains (Figure 1, panel d).”
- Awakening guardian angels: drugging the p53 pathway (2009, background): “This work has resulted in a spiro-oxindole derivative, MI-219, which shows good pharmacodynamics and bioavailability in mice compared with the initial spiro-oxindole compound”
- The diverse and complex roles of NF-κB subunits in cancer (2012, background): “Is this possible? A potential precedent exists with the p53 tumour suppressor, where compounds, such as nutlin 3, specifically disrupt the interaction between p53 and its negative regulator MDM2, leading to its accumulation in cancer cells that retain wild-type p53 (Ref”
- Blinded by the Light: The Growing Complexity of p53. (2009, background): “These types of drugs, some of which are in advanced stages of preclinical development or early clinical trials (Shangary and Wang, 2009), are predicted to show efficacy in tumors that retain wild-type p53.”