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