Small molecule agents targeting the p53-MDM2 pathway for cancer therapy.
The powerful tumor suppressor p53 takes charge of a regulatory network to guard over the living cells from harmful effect of different forms of stress and eradicate the tumor cells for normal physiological condition maintenance. However the antitumor function of p53 is often attenuated or even omitted mainly due to two alternative mechanisms, direct gene alterations in p53 or negative controlled by MDM2 protein. In this article, overview on different therapeutic strategies that are exploited to restore the neoplasm therapeutic effect to p53 will be provided, including pharmacological rescue of mutant p53 and modulation of the p53-MDM2 interaction. We attempt to focus on the medicinal chemistry aspects of small molecule agents targeting the p53-MDM2 pathway and recent progress in these agents. In addition, the mechanism of action and anticancer activity of different classes of compounds targeting the p53-MDM2 pathway, as well as structure-activity relationships, are discussed.
Ecole Normal Superieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Weisi
W
Wang
Yongzhou
Y
Hu
D000818:Animals; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2