title: Rational design and binding mode duality of MDM2-p53 inhibitors.
abstract: Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Gonzalez-Lopez de Turiso
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
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: Tiffany L
authors.initials: TL
authors.lastname: Correll
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Julian
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.forename: Mei-Chu
authors.initials: MC
authors.lastname: Lo
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.forename: Dustin
authors.initials: D
authors.lastname: McMinn
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
authors.forename: Tao
authors.initials: T
authors.lastname: Osgood
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Saiki
authors.forename: Steve
authors.initials: S
authors.lastname: Schneider
authors.forename: Paul
authors.initials: P
authors.lastname: Shaffer
authors.forename: Shou-Hua
authors.initials: SH
authors.lastname: Xiao
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: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002942:Circular Dichroism; D003461:Crystallography; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009025:Morpholines; D010880:Piperidines; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2