Structure-based design of potent non-peptide MDM2 inhibitors
Abstract
A successful structure-based design of a class of non-peptide small-molecule MDM2 inhibitors targeting the p53-MDM2 protein-protein interaction is reported. The most potent compound 1d binds to MDM2 protein with a Ki value of 86 nM and is 18 times more potent than a natural p53 peptide (residues 16-27). Compound 1d is potent in inhibition of cell growth in LNCaP prostate cancer cells with wild-type p53 and shows only a weak activity in PC-3 prostate cancer cells with a deleted p53. Importantly, 1d has a minimal toxicity to normal prostate epithelial cells. Our studies provide a convincing example that structure-based strategy can be employed to design highly potent, non-peptide, cell-permeable, small-molecule inhibitors to target protein-protein interaction, which remains a very challenging area in chemical biology and drug design.
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Spiro-oxindoles invented by Wang's laboratory constitute a new class of MDM2-p53 interaction antagonists developed using structure-based de novo design.
“Spiro-oxindoles invented by Wang's laboratory constitute is a new class of MDM2-p53 interaction antagonists that were developed using a structure-based de novo design strategy [39].”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [39]
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- Authors
- Ding, K., Lu, Y., Nikolovska-Coleska, Z., Qiu, S., Ding, Y., Gao, W., Stuckey, J., Krajewski, K., Roller, P. P., Tomita, Y., Parrish, D. A., Deschamps, J. R., & Wang, S.
- Affiliations
- National Institutes of Health (US)
- Departments of Internal Medicine and Medicinal Chemistry and Comprehensive Cancer Center, and Life Sciences Institute, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, Laboratory of Medicinal Chemistry, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C. 20007, The Laboratory for the Structure of Matter, Naval Research Laboratory, 4555 Overlook Avenue...
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-06-30
- Volume
- 127
- Issue
- 29
- Pages
- 10130-10131
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2054074966
- Cited by
- 657
- References
- 9
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 23 · 2023: 24 · 2022: 28 · 2021: 31 · 2020: 40 · 2019: 50 · 2018: 27 · 2017: 34 · 2016: 38 · 2015: 52 · 2014: 57 · 2013: 50 · 2012: 45
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- MDM2 inhibitors, structure-based drug design, prostate cancer, LNCaP cells, PC-3 cells, wild-type p53, cell-permeable inhibitors
- MeSH terms
- Models, Molecular, Nuclear Proteins, Proto-Oncogene Proteins, Spiro Compounds, Structure-Activity Relationship, Drug Design, Tumor Suppressor Protein p53, Crystallography, X-Ray, Indole Alkaloids, Biomimetic Materials, Proto-Oncogene Proteins c-mdm2
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