dc.contributor.author |
Jiang, Dadi |
en |
dc.contributor.author |
Tam, Arvin B |
en |
dc.contributor.author |
Alagappan, Muthuraman |
en |
dc.contributor.author |
Hay, Michael |
en |
dc.contributor.author |
Gupta, Aparna |
en |
dc.contributor.author |
Kozak, Margaret M |
en |
dc.contributor.author |
Solow-Cordero, David E |
en |
dc.contributor.author |
Lum, Pek Y |
en |
dc.contributor.author |
Denko, Nicholas C |
en |
dc.contributor.author |
Giaccia, Amato J |
en |
dc.contributor.author |
Le, Quynh-Thu |
en |
dc.contributor.author |
Niwa, Maho |
en |
dc.contributor.author |
Koong, Albert C |
en |
dc.date.accessioned |
2018-10-17T03:12:44Z |
en |
dc.date.issued |
2016-09 |
en |
dc.identifier.issn |
1535-7163 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/42573 |
en |
dc.description.abstract |
Using a luciferase reporter-based high-throughput chemical library screen and topological data analysis, we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as an inhibitor of the inositol requiring kinase 1α (IRE1α)-X-box binding protein-1 (XBP1) pathway of the unfolded protein response. We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships and identified N(9)-(3-(dimethylamino)propyl)-N(3),N(3),N(6),N(6)-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, whereas the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma cell survival, these analogues were cytotoxic to multiple myeloma cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing in vivo and the growth of multiple myeloma tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α-XBP1 inhibitors in the treatment of multiple myeloma. Mol Cancer Ther; 15(9); 2055-65. ©2016 AACR. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Molecular cancer therapeutics |
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. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Cell Line, Tumor |
en |
dc.subject |
Animals |
en |
dc.subject |
Humans |
en |
dc.subject |
Mice |
en |
dc.subject |
Multiple Myeloma |
en |
dc.subject |
Disease Models, Animal |
en |
dc.subject |
Acridines |
en |
dc.subject |
Endoribonucleases |
en |
dc.subject |
Protein-Serine-Threonine Kinases |
en |
dc.subject |
Antineoplastic Agents |
en |
dc.subject |
Drug Screening Assays, Antitumor |
en |
dc.subject |
Cluster Analysis |
en |
dc.subject |
Xenograft Model Antitumor Assays |
en |
dc.subject |
Gene Expression Profiling |
en |
dc.subject |
Signal Transduction |
en |
dc.subject |
Cell Survival |
en |
dc.subject |
Gene Expression Regulation, Neoplastic |
en |
dc.subject |
Drug Discovery |
en |
dc.subject |
High-Throughput Screening Assays |
en |
dc.subject |
X-Box Binding Protein 1 |
en |
dc.title |
Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1158/1535-7163.mct-15-1023 |
en |
pubs.issue |
9 |
en |
pubs.begin-page |
2055 |
en |
pubs.volume |
15 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
27307600 |
en |
pubs.end-page |
2065 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
research-article |
en |
pubs.subtype |
Journal Article |
en |
pubs.subtype |
Research Support, N.I.H., Extramural |
en |
pubs.elements-id |
531475 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1538-8514 |
en |
pubs.record-created-at-source-date |
2016-06-17 |
en |
pubs.dimensions-id |
27307600 |
en |