dc.contributor.author |
Sutherland, Hamish S |
|
dc.contributor.author |
Hwang, In Young |
|
dc.contributor.author |
Marshall, Elaine S |
|
dc.contributor.author |
Lindsay, Brent S |
|
dc.contributor.author |
Denny, William A |
|
dc.contributor.author |
Gilchrist, Catherine |
|
dc.contributor.author |
Joseph, Wayne R |
|
dc.contributor.author |
Greenhalgh, Debra |
|
dc.contributor.author |
Richardson, Emma |
|
dc.contributor.author |
Kestell, Philip |
|
dc.contributor.author |
Ding, Angela |
|
dc.contributor.author |
Baguley, Bruce C |
|
dc.coverage.spatial |
United States |
|
dc.date.accessioned |
2022-07-26T04:08:08Z |
|
dc.date.available |
2022-07-26T04:08:08Z |
|
dc.date.issued |
2012-10 |
|
dc.identifier.citation |
(2012). Investigational New Drugs, 30(5), 2035-2045. |
|
dc.identifier.issn |
0167-6997 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/60552 |
|
dc.description.abstract |
<h4>Purpose</h4>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.<h4>Methods</h4>Reactivation of p53 function was measured by flow cytometry as the ability to potentiate radiation-induced G(1)-phase cell cycle arrest and by western blotting to determine expression of p21(WAF1). DNA binding was measured by competition with ethidium and preliminary pharmacological and xenograft studies were carried out.<h4>Results</h4>Screening of analogues for potentiation of radiation-induced G(1)-phase cell cycle arrest using NZOV11, an ovarian tumour cell line containing a p53(R248Q) 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 p21(WAF1) 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.<h4>Conclusion</h4>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. |
|
dc.format.medium |
Print-Electronic |
|
dc.language |
eng |
|
dc.publisher |
Springer Nature |
|
dc.relation.ispartofseries |
Investigational new drugs |
|
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. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
|
dc.subject |
Cell Line, Tumor |
|
dc.subject |
Animals |
|
dc.subject |
Humans |
|
dc.subject |
Mice |
|
dc.subject |
Quinazolines |
|
dc.subject |
DNA Topoisomerases, Type II |
|
dc.subject |
DNA-Binding Proteins |
|
dc.subject |
Cell Cycle |
|
dc.subject |
Mutation |
|
dc.subject |
Tumor Suppressor Protein p53 |
|
dc.subject |
Mutant Proteins |
|
dc.subject |
Cyclin-Dependent Kinase Inhibitor p21 |
|
dc.subject |
Biotechnology |
|
dc.subject |
Cancer |
|
dc.subject |
Genetics |
|
dc.subject |
5.1 Pharmaceuticals |
|
dc.subject |
2 Aetiology |
|
dc.subject |
2.1 Biological and endogenous factors |
|
dc.subject |
5 Development of treatments and therapeutic interventions |
|
dc.subject |
Science & Technology |
|
dc.subject |
Life Sciences & Biomedicine |
|
dc.subject |
Oncology |
|
dc.subject |
Pharmacology & Pharmacy |
|
dc.subject |
TP53 mutation |
|
dc.subject |
Quinazoline synthesis |
|
dc.subject |
Cell cycle arrest |
|
dc.subject |
Flow cytometry |
|
dc.subject |
Tumour growth delay |
|
dc.subject |
WILD-TYPE |
|
dc.subject |
IN-VITRO |
|
dc.subject |
DNA |
|
dc.subject |
CP-31398 |
|
dc.subject |
RESISTANCE |
|
dc.subject |
BINDING |
|
dc.subject |
GROWTH |
|
dc.subject |
1112 Oncology and Carcinogenesis |
|
dc.subject |
Biomedical |
|
dc.subject |
Basic Science |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.title |
Therapeutic reactivation of mutant p53 protein by quinazoline derivatives. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1007/s10637-011-9744-z |
|
pubs.issue |
5 |
|
pubs.begin-page |
2035 |
|
pubs.volume |
30 |
|
dc.date.updated |
2022-06-16T04:21:04Z |
|
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
21912889 (pubmed) |
|
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/21912889 |
|
pubs.end-page |
2045 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
Journal Article |
|
pubs.elements-id |
225024 |
|
pubs.org-id |
Medical and Health Sciences |
|
pubs.org-id |
Science |
|
pubs.org-id |
Science Research |
|
pubs.org-id |
Medical Sciences |
|
pubs.org-id |
Auckland Cancer Research |
|
pubs.org-id |
School of Medicine |
|
pubs.org-id |
Paediatrics Child & Youth Hlth |
|
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
|
dc.identifier.eissn |
1573-0646 |
|
pubs.record-created-at-source-date |
2022-06-16 |
|
pubs.online-publication-date |
2012-10 |
|