title: Structure-based design of novel inhibitors of the MDM2-p53 interaction.
abstract: Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.forename: Felix
authors.initials: F
authors.lastname: Gonzalez-Lopez De Turiso
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Hilary P
authors.initials: HP
authors.lastname: Beck
authors.forename: Jude
authors.initials: J
authors.lastname: Canon
authors.forename: Ada
authors.initials: A
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Chow
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deignan
authors.forename: Brian M
authors.initials: BM
authors.lastname: Fox
authors.forename: Darin
authors.initials: D
authors.lastname: Gustin
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Xianyun
authors.initials: X
authors.lastname: Jiao
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.forename: David J
authors.initials: DJ
authors.lastname: Kopecky
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.forename: Mei-Chu
authors.initials: MC
authors.lastname: Lo
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
authors.forename: Tao
authors.initials: T
authors.lastname: Osgood
authors.forename: Mark
authors.initials: M
authors.lastname: Ragains
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Saiki
authors.forename: Steve
authors.initials: S
authors.lastname: Schneider
authors.forename: Maria
authors.initials: M
authors.lastname: Toteva
authors.forename: Peter
authors.initials: P
authors.lastname: Yakowec
authors.forename: Xuelei
authors.initials: X
authors.lastname: Yan
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.forename: Dongyin
authors.initials: D
authors.lastname: Yu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.forename: Steven H
authors.initials: SH
authors.lastname: Olson
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D010881:Piperidones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis
chemical_list: C575269:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D010881:Piperidones; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D020741:rho GTP-Binding Proteins