5-deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2

Dickens, M.P., Roxburgh, P. , Hock, A., Mezna, M., Kellam, B., Vousden, K.H. and Fischer, P.M. (2013) 5-deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2. Bioorganic and Medicinal Chemistry, 21(22), pp. 6868-6877. (doi: 10.1016/j.bmc.2013.09.038)

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Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure–activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Hock, Dr Andreas and Mezna, Dr Mokdad and Vousden, Karen and Roxburgh, Dr Patricia
Authors: Dickens, M.P., Roxburgh, P., Hock, A., Mezna, M., Kellam, B., Vousden, K.H., and Fischer, P.M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Bioorganic and Medicinal Chemistry
Publisher:Elsevier Ltd.
ISSN (Online):1464-3391
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in Bioorganic & Medicinal Chemistry 21(22):6868-6877
Publisher Policy:Reproduced under a Creative Commons License

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