Investigation of the inhibitory mechanism of apomorphine against MDM2–p53 interaction
Abstract
Mirror-image screening using d-proteins is a powerful approach to provide mirror-image structures of chiral natural products for drug screening. During the course of our screening study for novel MDM2-p53 interaction inhibitors, we identified that NPD6878 (R-(-)-apomorphine) inhibited both the native l-MDM2-l-p53 interaction and the mirror-image d-MDM2-d-p53 interaction at equipotent doses. In addition, both enantiomers of apomorphine showed potent inhibitory activity against the native MDM2-p53 interaction. In this study, we investigated the inhibitory mechanism of both enantiomers of apomorphine against the MDM2-p53 interaction. Achiral oxoapomorphine, which was converted from chiral apomorphines under aerobic conditions, served as the reactive species to form a covalent bond at Cys77 of MDM2, leading to the inhibitory effect against the binding to p53.
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In 2017, Ishiba et al. revealed NPD6878 (apomorphine) as an MDM2-p53 inhibitor candidate with high potency.
“In 2017, Ishiba et al. performed mirror-image screening through D-proteins, which is an approach for identifying potential pharmaceutical candidates from homochiral resources, and revealed that NPD6878 (apomorphine) (75) was an MDM2–p53 inhibitor candidate with high potency.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [218]
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- Authors
- Ishiba, H., Noguchi, T., Shu, K., Ohno, H., Honda, K., Kondoh, Y., Osada, H., Fujii, N., & Oishi, S.
- Affiliations
- Kyoto University (JP)
- RIKEN Center for Sustainable Resource Science (JP)
- Corresponding author
- Oishi, Shinya
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 27
- Issue
- 11
- Pages
- 2571-2574
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2599047524
- Cited by
- 10
- References
- 28
- Citations by year
- 2023: 1 · 2022: 3 · 2020: 4 · 2019: 1 · 2018: 1
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- JSPS (24659046, 15H04653, 26-7738)
- MEXT
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- apomorphine, p53-MDM2 interaction, D-proteins, enantiomers, covalent inhibition, protein-protein interaction inhibitors, chiral natural products
- MeSH terms
- Apomorphine, Humans, Protein Binding, Stereoisomerism, Structure-Activity Relationship, Tumor Suppressor Protein p53, Surface Plasmon Resonance, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2
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