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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

Citation

Azimi, I and Flanagan, JU and Stevenson, RJ and Inserra, M and Vetter, I and Monteith, GR and Denny, WA, 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, Bioorganic and Medicinal Chemistry, 25, (1) pp. 440-449. ISSN 0968-0896 (2017) [Refereed Article]

Copyright Statement

2016 Elsevier Ltd. All rights reserved.

DOI: doi:10.1016/j.bmc.2016.11.007

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 Details

Item Type:Refereed Article
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.
Research Division:Medical and Health Sciences
Research Group:Pharmacology and Pharmaceutical Sciences
Research Field:Pharmacology and Pharmaceutical Sciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:Azimi, I (Dr Iman Azimi)
ID Code:124404
Year Published:2017
Web of Science® Times Cited:4
Deposited By:Pharmacy
Deposited On:2018-02-21
Last Modified:2018-04-13
Downloads:0

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