Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors

Zhao, Yujun; Liu, Liu; Sun, Wei; Lu, Jianfeng; McEachern, Donna; Li, Xiaoqin,; Yu, Shanghai; Bernard, Denzil; Ochsenbein, Philippe; Ferey, Vincent; Carry, Jean-Christophe; Deschamps, Jeffrey R.; Sun, Duxin; Wang, Shaomeng

doi:10.1021/ja3125417

Cited by 234Cancer-related Molecular PathwaysSynthesis and biological activityHeat shock proteins research

Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors

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Zhao, Yujun, Liu, Liu, Sun, Wei, Lu, Jianfeng, McEachern, Donna, Li, Xiaoqin,, Yu, Shanghai, Bernard, Denzil +6 more·2013·Journal of the American Chemical Society

DOI 10.1021/ja3125417PMC PMC3806051

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Abstract

Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.

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Appropriate stereochemistry is critical for good binding affinity in spirocyclic oxindole-based MDM2 inhibitors.
“In spirocyclic oxindole-based MDM2 inhibitors, the oxindole fragment occupies the Trp23-containing cleft of P53, and appropriate stereochemistry is critical for good binding affinity73,74.”
From Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma (2020) · cites this paper as [74]
In spirocyclic oxindole-based MDM2 inhibitors, the oxindole fragment occupies the Trp23-containing cleft of P53.
“In spirocyclic oxindole-based MDM2 inhibitors, the oxindole fragment occupies the Trp23-containing cleft of P53, and appropriate stereochemistry is critical for good binding affinity73,74.”
From Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma (2020) · cites this paper as [74]

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Authors: Zhao, Y., Liu, L., Sun, W., Lu, J., McEachern, D., Li, X., Yu, S., Bernard, D., Ochsenbein, P., Ferey, V., Carry, J.-C., Deschamps, J. R., Sun, D., & Wang, S.
Affiliations: University of Michigan (US)
United States Naval Research Laboratory (US)
Sanofi (France) (FR)
Corresponding author: Wang, Shaomeng
ORCID: Zhao, Yujun
Liu, Liu
Sun, Wei
McEachern, Donna
Li, Xiaoqin,
Yu, Shanghai
Bernard, Denzil
Ochsenbein, Philippe
Ferey, Vincent
Carry, Jean-Christophe
Deschamps, Jeffrey R.
Sun, Duxin
Wang, Shaomeng
Venue: Journal of the American Chemical Society
Publisher: American Chemical Society (ACS)
Published: 2013-05-03
Volume: 135
Issue: 19
Pages: 7223-7234
ISSN: 0002-7863 (ISSN-L)
1520-5126
DOI: 10.1021/ja3125417
PMC: PMC3806051
OpenAlex: W1971921242
Cited by: 234
References: 25
Citations by year: 2026: 11 · 2025: 13 · 2024: 17 · 2023: 18 · 2022: 18 · 2021: 16 · 2020: 19 · 2019: 18 · 2018: 20 · 2017: 14 · 2016: 19 · 2015: 14 · 2014: 27 · 2013: 10
FWCI: 13.56
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Journal of the American Chemical Society (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Sanofi
University of Michigan
National Institute on Drug Abuse
National Cancer Institute (P50CA097248, P50CA06956, R01CA121279, P30CA046592)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords: MDM2 inhibitors, spirooxindoles, diastereomers, stereochemistry, p53-MDM2 interaction, ring-opening cyclization, small molecule inhibitors, cancer therapy, tumor regression
MeSH terms: Oxindoles, Animals, Antineoplastic Agents, Bone and Bones, Bone Neoplasms, Cyclization, Humans, Indoles, Models, Molecular, Osteosarcoma, Spiro Compounds, Stereoisomerism, Mice, SCID, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2

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Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors

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