Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives
Open accessAbstract
Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.
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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 [16]
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References 135 · Cited by 106
Research works printed but not linked: 2
- [15]Bauer T. Hong D. Somaiah N. Cai C. Song S. Kumar P. Abstract B27: a phase I dose escalation study of MDM2 inhibitor DS-3032b in patients with hematological malignancies-preliminary results. AACR-NCI-EORTC international conference: molecular targets and cancer; 2015, Nov. 5–9; Boston, MA, USA Mol Cancer Ther 14 12 Suppl 2 2015 abstract nr B27
- [102]Wang S. Sun W. Zhao Y. McEachern D. Meaux I. Barriere C. An optimized inhibitor of MDM2–P53 interaction that induces complete and durable tumor regression Cancer Res 74 2014 5855 5865 25145672 PMC4247201
- Authors
- Fang, Y., Liao, G., & Yu, B.
- Affiliations
- Guangzhou University of Chinese Medicine (CN)
- Zhengzhou University (CN)
- Corresponding author
- Liao, Guochao
- Yu, Bin
- Venue
- Acta Pharmaceutica Sinica B
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 10
- Issue
- 7
- Pages
- 1253-1278
- ISSN
- 2211-3835 (ISSN-L)
- PMC
- PMC7452049
- OpenAlex
- W2999596427
- Cited by
- 106
- References
- 135
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 22 · 2023: 12 · 2022: 21 · 2021: 17 · 2020: 4
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme
- Guangdong Provincial Key Laboratory for Translational Cancer Research of Chinese Medicine, Guangzhou University of Chinese Medicine (2018B030322011)
- China Postdoctoral Science Foundation (2018M630840, 2019T120641)
- National Natural Science Foundation of China (81703326, 81773580, 81973177)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- MDM2 inhibitors, PROTAC degraders, p53 activation, small molecule inhibitors, structure-activity relationship, RG7112, RG7388, acquired drug resistance, cancer therapy
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