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An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay

Stevenson, RJ, Azimi, I ORCID: 0000-0001-9477-9999, Flanagan, JU, Inserra, FG, Vetter, I, Monteith, GR and Denny, WA 2018 , 'An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay' , Bioorganic & medicinal chemistry , pp. 1-8 , doi: 10.1016/j.bmc.2018.05.012.

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Abstract

The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.

Item Type: Article
Authors/Creators:Stevenson, RJ and Azimi, I and Flanagan, JU and Inserra, FG and Vetter, I and Monteith, GR and Denny, WA
Keywords: Orai1, store-operated calcium entry, breast cancer
Journal or Publication Title: Bioorganic & medicinal chemistry
Publisher: Pergamon-Elsevier Science Ltd
ISSN: 0968-0896
DOI / ID Number: 10.1016/j.bmc.2018.05.012
Copyright Information:

Copyright 2018 Elsevier Ltd.

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