5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2.

Abstract

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.

• Authors: Michael P Dickens, Patricia Roxburgh, Andreas Hock, Mokdad Mezna, Barrie Kellam, Karen H Vousden, Peter M Fischer
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 22 Pg. 6868-77 (Nov 15 2013) ISSN: 1464-3391 [Electronic] England
• PMID: 24113239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Flavins
• Tumor Suppressor Protein p53
• 5-deazaflavin
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Binding Sites
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (chemical synthesis, chemistry, metabolism, pharmacology)
• Flavins (chemical synthesis, chemistry, metabolism, pharmacology)
• Humans
• Molecular Docking Simulation
• Protein Binding
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitination