title: Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.
abstract: We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Shanghai
authors.initials: S
authors.lastname: Yu
authors.forename: Dongguang
authors.initials: D
authors.lastname: Qin
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Shangary
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Guoping
authors.initials: G
authors.lastname: Wang
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Su
authors.initials: S
authors.lastname: Qiu
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.forename: Rebecca
authors.initials: R
authors.lastname: Miller
authors.forename: Sanmao
authors.initials: S
authors.lastname: Kang
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C543589:MI-63 compound; D009025:Morpholines; D010879:Piperazines; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2