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Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold

Lookup NU author(s): Dr Ian Hardcastle, Shafiq Ahmed, Helen Atkins, Gillian Farnie, Professor Bernard Golding, Professor Roger Griffin, Sabrina Guyenne, Dr Claire Hutton, Stuart Kemp, Professor Herbie Newell, Dr Stefano Norbedo, Dr Julian Scott Northen, Rebecca Reid, Dr Kappusamy Saravanan, Professor John Lunec

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Abstract

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. © 2006 American Chemical Society.


Publication metadata

Author(s): Hardcastle, I.R., Ahmed, S., Atkins, H., Farnie, G., Golding, B.T., Griffin, R.J., Guyenne, S., Hutton,C., Källblad, P., Kemp, S., Kitching, M.S., Newell, D.R., Norbedo, S., Northen, J.S., Reid, R.J., Saravanan, K., Willems, H., Lunec, J.

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2006

Volume: 49

Issue: 21

Pages: 6209-6221

Print publication date: 01/10/2006

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm0601194

DOI: 10.1021/jm0601194


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