Small-Molecule Inhibitors of the MDM2-p53 Protein−Protein Interaction Based on an Isoindolinone Scaffold

• Published in: Journal of medicinal chemistry Vol. 49; no. 21; pp. 6209 - 6221
• Main Authors: Hardcastle, Ian R, Ahmed, Shafiq U, Atkins, Helen, Farnie, Gillian, Golding, Bernard T, Griffin, Roger J, Guyenne, Sabrina, Hutton, Claire, Källblad, Per, Kemp, Stuart J, Kitching, Martin S, Newell, David R, Norbedo, Stefano, Northen, Julian S, Reid, Rebecca J, Saravanan, K, Willems, Henriëtte M. G, Lunec, John
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.10.2006; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chemistry, Medicinal; Combinatorial Chemistry Techniques; Drug Screening Assays, Antitumor; General aspects; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Proto-Oncogene Proteins c-mdm2 - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Transcription, Genetic; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; P53-HDM2 INTERACTION; ONCOGENE; NOVO LIGAND DESIGN; DOCKING; P53 PATHWAY; TUMOR-CELL-LINES; ANTAGONISTS; ASSOCIATION; DISCOVERY; STRUCTURE-BASED DESIGN; Gene product; p53 Protein; Rodentia; Lactam; Molecular interaction; In vitro; Isoindole derivatives; mdm2 Gene; Vertebrata; Mammalia; TP53 Gene; Structure activity relation; Mouse; Animal; Chlorine Organic compounds; Binding mode; Inhibitor; Small molecule; Onc gene; Chemical synthesis; Tumor suppressor gene
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0601194

From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC50 = 15.9 ± 0.8 μM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC50 = 5.3 ± 0.9 μM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.