The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy

Eur J Med Chem. 2018 Nov 5:159:1-9. doi: 10.1016/j.ejmech.2018.09.044. Epub 2018 Sep 18.


In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed.

Keywords: AMG-232; Cancer therapy; MDM2 inhibitors; MDM2-p53 interactions; Piperidinones.

Publication types

  • Review

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Piperidones / chemical synthesis
  • Piperidones / chemistry
  • Piperidones / pharmacology*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism


  • Ligands
  • Piperidones
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2