The initial evaluation of non-peptidic small-molecule HDM2 inhibitors based on p53-HDM2 complex structure

Cancer Lett. 2002 Sep 8;183(1):69-77. doi: 10.1016/s0304-3835(02)00084-8.

Abstract

Peptidic Mouse Double Minute (MDM2) inhibitors have been demonstrated to effectively inhibit the interaction between p53 and MDM2, thus providing a therapeutic strategy for some tumors. However, there is no report on non-peptidic inhibitors. In this study non-peptidic HDM2 (the human homologue of MDM2) inhibitors were obtained by computer-aided design and subsequently synthesized by chemical method. Bio-evaluation showed that some of these inhibitors have affinity with HDM2, and can cause death of some tumor cells which express wild-type p53. Cellular assays showed that one of these compounds, syc-7, can activate the p53 pathway in some of these tumor cell lines, and further induce apoptosis. The results suggest that developing non-peptidic small-molecule HDM2 inhibitors is a promising way for new antitumor drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Breast Neoplasms
  • Carcinoma, Small Cell
  • Cell Survival / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • HeLa Cells
  • Humans
  • Lung Neoplasms
  • Neoplasm Proteins / antagonists & inhibitors*
  • Nuclear Proteins*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*

Substances

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