Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction

J Med Chem. 2014 Dec 26;57(24):10499-511. doi: 10.1021/jm501550p. Epub 2014 Dec 4.

Abstract

Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Drug Discovery*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Protein Binding / drug effects*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2

Associated data

  • PDB/4WT2