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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

Item Type:	Article
Authors/Creators:	Azimi, I and Flanagan, JU and Stevenson, RJ and Inserra, M and Vetter, I and Monteith, GR and Denny, WA
Keywords:	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.
Journal or Publication Title:	Bioorganic and Medicinal Chemistry
Publisher:	Pergamon-Elsevier Science Ltd
ISSN:	0968-0896
DOI / ID Number:	10.1016/j.bmc.2016.11.007
Copyright Information:	© 2016 Elsevier Ltd. All rights reserved.
Related URLs:	Google Scholar: Azimi, I
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