Abstract
As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Clinical Trials, Phase I as Topic
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Drug Discovery
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Humans
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Isoquinolines / chemical synthesis*
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Isoquinolines / pharmacokinetics
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Isoquinolines / pharmacology*
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology*
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Rats
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / genetics*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Isoquinolines
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NVP-CGM097
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Piperazines
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-mdm2