Therapeutic reactivation of mutant p53 protein by quinazoline derivatives

Show simple item record Sutherland, Hamish en Hwang, IY en Marshall, ES en Lindsay, BS en Denny, William en Gilchrist, Catherine en Joseph, Wayne en Greenhalgh, D en Richardson, E en Kestell, P en Ding, A en Baguley, Bruce en 2011-11-18T02:17:13Z en 2011 en
dc.identifier.citation Investigational New Drugs Online First:1-11 2011 en
dc.identifier.issn 0167-6997 en
dc.identifier.uri en
dc.description.abstract Purpose The human tumour suppressor protein p53 is mutated in nearly half of human tumours and most mutant proteins have single amino acid changes. Several drugs including the quinazoline derivative 1 (CP-31398) have been reported to restore p53 activity in mutant cells. The side chain of 1 contains a styryl linkage that compromises its stability and we wished to explore the activity of analogues containing more stable side chains. Methods Reactivation of p53 function was measured by flow cytometry as the ability to potentiate radiation-induced G1-phase cell cycle arrest and by western blotting to determine expression of p21WAF1. DNA binding was measured by competition with ethidium and preliminary pharmacological and xenograft studies were carried out. Results Screening of analogues for potentiation of radiation-induced G1-phase cell cycle arrest using NZOV11, an ovarian tumour cell line containing a p53R248Q mutation, demonstrated that the (2-benzofuranyl)-quinazoline derivative 5 was among the most active of the analogues. Compound 5 showed similar effects in several other p53 mutant human tumour cell lines but not in a p53 null cell line. 5 also potentiated p21WAF1 expression induced by radiation. DNA binding affinity was measured and found to correlate with p53 reactivation activity. Plasma concentrations of 5 in mice were sufficient to suggest in vivo activity and a small induced tumour growth delay (7 days) of NZM4 melanoma xenografts was observed. Conclusion Compound 5 restores p53-like function to a human tumour cells lines expressing a variety of mutant p53 proteins, thus providing a basis for the design of further new drugs. en
dc.publisher Springer Science+Business Media, LLC en
dc.relation.ispartofseries Investigational New Drugs en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.title Therapeutic reactivation of mutant p53 protein by quinazoline derivatives en
dc.type Journal Article en
dc.identifier.doi 10.1007/s10637-011-9744-z en
pubs.begin-page 1 en
pubs.volume Online First en
dc.rights.holder Copyright: Springer Science+Business Media, LLC en
pubs.end-page 11 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 228416 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en School of Medicine en Paediatrics Child & Youth Hlth en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1573-0646 en
pubs.record-created-at-source-date 2011-11-18 en

Files in this item

There are no files associated with this item.

Find Full text

This item appears in the following Collection(s)

Show simple item record


Search ResearchSpace