期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 19, 页码 7223-7234出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja3125417
关键词
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资金
- National Cancer Institute, National Institutes of Health [R01CA121279, P50CA06956, P50CA097248]
- University of Michigan Cancer Center [P30CA046592]
- Ascenta Therapeutics, Inc.
- Sanofi S.A.
- NIDA [ADA12003-001]
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 K-i value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.
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