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Targeting p53-MDM2-MDMX loop for cancer therapy
Qi Zhang1, Shelya X Zeng, Hua Lu
1Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Ave, Louisiana, LA, 70112, USA.
Abstract:
The tumor suppressor p53 plays a central role in anti-tumorigenesis and cancer therapy. It has been described as "the guardian of the genome", because it is essential for conserving genomic stability by preventing mutation, and its mutation and inactivation are highly related to all human cancers. Two important p53 regulators, MDM2 and MDMX, inactivate p53 by directly inhibiting its transcriptional activity and mediating its ubiquitination in a feedback fashion, as their genes are also the transcriptional targets of p53. On account of the importance of the p53-MDM2-MDMX loop in the initiation and development of wild type p53-containing tumors, intensive studies over the past decade have been aiming to identify small molecules or peptides that could specifically target individual protein molecules of this pathway for developing better anti-cancer therapeutics. In this chapter, we review the approaches for screening and discovering efficient and selective MDM2 inhibitors with emphasis on the most advanced synthetic small molecules that interfere with the p53-MDM2 interaction and are currently on Phase I clinical trials. Other therapeutically useful strategies targeting this loop, which potentially improve the prospects of cancer therapy and prevention, will also be discussed briefly.
Insights
The tumor suppressor p53, crucial for genomic stability, is often inactivated in cancer. Researchers are developing small molecules to target its regulators, MDM2 and MDMX, for novel cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The tumor suppressor p53 is vital for preventing cancer by maintaining genomic stability.
- MDM2 and MDMX are key regulators that inactivate p53, and their dysregulation is linked to various human cancers.
- The p53-MDM2-MDMX feedback loop is critical in the development of tumors with wild-type p53.
Purpose of the Study:
- To review strategies for discovering selective inhibitors of MDM2.
- To highlight advanced small molecules targeting the p53-MDM2 interaction in clinical trials.
- To discuss other therapeutic approaches for the p53-MDM2-MDMX pathway.
Main Methods:
- Review of literature on screening and discovery of MDM2 inhibitors.
- Focus on synthetic small molecules interfering with p53-MDM2 interaction.
- Discussion of therapeutic strategies targeting the p53-MDM2-MDMX loop.
Main Results:
- Intensive research has focused on identifying small molecules and peptides targeting the p53-MDM2-MDMX pathway.
- Several advanced synthetic small molecules inhibiting the p53-MDM2 interaction are in Phase I clinical trials.
- Various strategies targeting this loop show promise for cancer therapy and prevention.
Conclusions:
- Targeting the p53-MDM2-MDMX pathway offers a promising avenue for cancer treatment.
- Selective MDM2 inhibitors are advancing through clinical trials.
- Further exploration of this pathway could lead to improved cancer therapies.
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