Evaluation of known and novel inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a Fluorescence Imaging Plate Reader assay.

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dc.contributor.author Azimi, Iman en
dc.contributor.author Flanagan, Jack en
dc.contributor.author Stevenson, Ralph en
dc.contributor.author Inserra, Marco en
dc.contributor.author Vetter, Irina en
dc.contributor.author Monteith, Gregory R en
dc.contributor.author Denny, William en
dc.date.accessioned 2018-10-24T22:07:49Z en
dc.date.issued 2017-01 en
dc.identifier.issn 0968-0896 en
dc.identifier.uri http://hdl.handle.net/2292/43405 en
dc.description.abstract The Orai1 Ca2+ permeable ion channel is an important component of store operated Ca2+ entry (SOCE) in cells. It's over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays. The assay was also used in a screening project seeking novel inhibitors. Following a broad literature survey of classes of calcium channel inhibitors we used simplified ligand structures to query the ZINC on-line database, and following two iterations of refinement selected a novel Orai1-selective dichlorophenyltriazole hit compound. Analogues of this were synthesized and evaluated in the FLIPR assay to develop structure-activity relationships (SAR) for the three domains of the hit; triazole (head), dichlorophenyl (body) and substituted phenyl (tail). For this series, the results suggested the need for a lipophilic tail domain and an out-of-plane twist between the body and tail domains. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries Bioorganic & medicinal chemistry 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 Humans en
dc.subject Triazoles en
dc.subject Calcium Channel Blockers en
dc.subject Drug Stability en
dc.subject Structure-Activity Relationship en
dc.subject Stereoisomerism en
dc.subject Fluorescence en
dc.subject High-Throughput Screening Assays en
dc.subject HEK293 Cells en
dc.subject Databases, Chemical en
dc.subject ORAI1 Protein en
dc.title Evaluation of known and novel inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a Fluorescence Imaging Plate Reader assay. en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.bmc.2016.11.007 en
pubs.issue 1 en
pubs.begin-page 440 en
pubs.volume 25 en
dc.rights.holder Copyright: The author en
dc.identifier.pmid 27856238 en
pubs.end-page 449 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype Journal Article en
pubs.elements-id 547034 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 Pharmacology en
pubs.org-id Science en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1464-3391 en
pubs.record-created-at-source-date 2016-11-19 en
pubs.dimensions-id 27856238 en

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