Small-molecule MDM2-p53 inhibitors: recent advances.
Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.
Newcastle Cancer Centre, School of Chemistry, Bedson Building, Newcastle University, NE1 7RU, UK.
Bian
B
Zhang
Bernard T
BT
Golding
Ian R
IR
Hardcastle
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000078183:Oxindoles; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D060066:Protein Interaction Maps / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D062366:para-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D000078183:Oxindoles; D010879:Piperazines; D011759:Pyrrolidines; C586849:RG7388; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; C482204:nutlin 2; D062366:para-Aminobenzoates; C022960:2-oxindole; D051736:Proto-Oncogene Proteins c-mdm2