Targeting the MDM2–p53 Protein–Protein Interaction for New Cancer Therapy: Progress and Challenges
Open accessAbstract
MDM2 is a primary cellular inhibitor of p53. It inhibits p53 function by multiple mechanisms, each of which, however, is mediated by their direct interaction. It has been proposed that small-molecule inhibitors designed to block the MDM2-p53 interaction may be effective in the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at least seven such compounds have now been advanced into human clinical trials as new anticancer drugs. This review offers a perspective on the design and development of MDM2 small-molecule inhibitors and discusses early clinical data for some of the MDM2 small-molecule inhibitors and future challenges for the successful clinical development of MDM2 inhibitors for cancer treatment.
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Nine MDM2 inhibitors have entered clinical trials: RG7112, RG7388/RO6839921, MK-8242, AMG232, SAR405838, DS-3032b, HDM201, NVP-CGM097 and APG-115.
“According to these three clear binding sites, a variety of structural types of MDM2 inhibitors have been reported, among which nine have entered clinical trials (RG7112, RG7388/RO6839921, MK-8242, AMG232, SAR405838, DS-3032b, HDM201, NVP-CGM097 and APG-115) (Fig. 3), with a variety of scaffold types [15–18].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [15]
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- Authors
- Wang, S., Zhao, Y., Aguilar, A., Bernard, D., & Yang, C.-Y.
- Affiliations
- University of Michigan (US)
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-03-07
- Volume
- 7
- Issue
- 5
- Pages
- a026245
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC5411684
- OpenAlex
- W2594386026
- Cited by
- 300
- References
- 41
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 18 · 2023: 40 · 2022: 44 · 2021: 50 · 2020: 39 · 2019: 30 · 2018: 20 · 2017: 9 · 2016: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Susan G. Komen for the Cure
- Prostate Cancer Foundation
- Sanofi
- Ascentage Pharma
- National Institutes of Health
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, p53, p53-MDM2 interaction, small molecule inhibitors, p53 reactivation, tumor suppressor function, anticancer drug development, clinical trials, cancer therapy
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Indoles, Neoplasms, Protein Binding, Spiro Compounds, Tumor Suppressor Protein p53, Imidazolines, Proto-Oncogene Proteins c-mdm2
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