title: The initial evaluation of non-peptidic small-molecule HDM2 inhibitors based on p53-HDM2 complex structure.
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.
authors.affiliation: National Laboratory of Molecular Oncology, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, P.O.Box 2258, 100021, P.R., Beijing, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhao
authors.forename: Mijuan
authors.initials: M
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Aiping
authors.initials: A
authors.lastname: Luo
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Dali
authors.initials: D
authors.lastname: Yin
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D018288:Carcinoma, Small Cell; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051736:Proto-Oncogene Proteins c-mdm2; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2