title: Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency.
abstract: Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 ± 0.01 μM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 ± 0.02 μM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle NE1 7RU, United Kingdom. i.r.hardcastle@ncl.ac.uk
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Junfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Eric
authors.initials: E
authors.lastname: Valeur
authors.forename: Anna
authors.initials: A
authors.lastname: Watson
authors.forename: Shafiq U
authors.initials: SU
authors.lastname: Ahmed
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Blackburn
authors.forename: Karim
authors.initials: K
authors.lastname: Bennaceur
authors.forename: William
authors.initials: W
authors.lastname: Clegg
authors.forename: Catherine
authors.initials: C
authors.lastname: Drummond
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Jan
authors.initials: J
authors.lastname: Gruber
authors.forename: Karen
authors.initials: K
authors.lastname: Haggerty
authors.forename: Ross W
authors.initials: RW
authors.lastname: Harrington
authors.forename: Claire
authors.initials: C
authors.lastname: Hutton
authors.forename: Stuart
authors.initials: S
authors.lastname: Kemp
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Lu
authors.forename: James M
authors.initials: JM
authors.lastname: McDonnell
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Sara L
authors.initials: SL
authors.lastname: Payne
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Revill
authors.forename: Christiane
authors.initials: C
authors.lastname: Riedinger
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: John
authors.initials: J
authors.lastname: Lunec
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D054833:Isoindoles; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2