Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development

J Med Chem. 2013 Jul 25;56(14):5979-83. doi: 10.1021/jm400487c. Epub 2013 Jul 16.

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

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Drug Discovery
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • para-Aminobenzoates / chemical synthesis*
  • para-Aminobenzoates / pharmacology
  • para-Aminobenzoates / therapeutic use

Substances

  • Antineoplastic Agents
  • Pyrrolidines
  • RG7388
  • Tumor Suppressor Protein p53
  • para-Aminobenzoates
  • Proto-Oncogene Proteins c-mdm2