Abstract
MDM2 is a key oncogenic protein that serves as a negative regulator of the tumor suppressor p53. While a number of inhibitors of the MDM2-p53 interaction have progressed to clinical testing as treatments for a variety of hematologic and solid tumor cancers, the results thus far have been mixed, with perhaps the strongest responses observed in relapsed/refractory acute myeloid leukemia (AML). In an effort to improve the efficacy for this class of compounds, researchers have turned to targeted degradation of MDM2. IMiD-based MDM2 PROTAC 8, which potently reduces MDM2 protein levels through targeted degradation, exhibits enhanced efficacy in the RS4;11 xenograft model relative to a nondegrading MDM2-p53 inhibitor MI-1061.
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Indoles / chemistry
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Indoles / pharmacology
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Indoles / therapeutic use
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / pathology
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Protein Interaction Domains and Motifs
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology
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Spiro Compounds / therapeutic use
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays
Substances
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4-(6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxodispiro(cyclohexane-1,2'-pyrrolidine-3',3''-indoline)-5'-carboxamido)benzoic acid
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Indoles
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Spiro Compounds
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-mdm2