title: Inhibitors of MDM2 and MDMX: a structural perspective.
abstract: p53 is a potent tumor suppressor with a crucial role in preventing uncontrolled cell proliferation and is therefore frequently deleted or mutated in cancer. For tumors with wild-type p53, its function can be overcome by overactive cellular antagonists, such as the ubiquitin ligase murine double minute clone 2 (MDM2). Restoring p53 activity by inhibiting MDM2 in such cancers can eradicate tumors. Consequently, the MDM2-p53 interaction has been extensively targeted for inhibition by small molecules. In recent years, MDM2-like protein (MDMX), another key downregulator of p53, has gained increasing importance as an additional target for drug development, in order to provide a complementary approach to MDM2 inhibition. In this review, we describe how detailed structural knowledge of the MDM2-p53 interface and, more recently, of the MDMX-p53 interaction have helped advance the development of inhibitors against the two targets. We present a summary of the functional biochemistry of MDM2, MDMX and p53 as well as their interactions and examine recent progress in the development of inhibitors of MDM2 and MDMX.
authors.affiliation: Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK. christiane.riedinger@bioch.ox.ac.uk
authors.forename: Christiane
authors.initials: C
authors.lastname: Riedinger
authors.forename: James M
authors.initials: JM
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D001688:Biological Products; D007211:Indoles; D008024:Ligands; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2