Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction

J Med Chem. 2006 Jun 15;49(12):3432-5. doi: 10.1021/jm051122a.

Abstract

Potent, specific, non-peptide small-molecule inhibitors of the MDM2-p53 interaction were successfully designed. The most potent inhibitor (MI-63) has a K(i) value of 3 nM binding to MDM2 and greater than 10,000-fold selectivity over Bcl-2/Bcl-xL proteins. MI-63 is highly effective in activation of p53 function and in inhibition of cell growth in cancer cells with wild-type p53 status. MI-63 has excellent specificity over cancer cells with deleted p53 and shows a minimal toxicity to normal cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Models, Molecular
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Indoles
  • Spiro Compounds
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2