Abstract
Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Drug Discovery
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacology
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Pyrrolidines / therapeutic use
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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para-Aminobenzoates / chemical synthesis*
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para-Aminobenzoates / pharmacology
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para-Aminobenzoates / therapeutic use
Substances
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Antineoplastic Agents
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Pyrrolidines
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RG7388
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Tumor Suppressor Protein p53
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para-Aminobenzoates
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Proto-Oncogene Proteins c-mdm2