Drug repurposing against the store-operated calcium entry (SOCE) pathway and subsequent exploration of SOCE in oligodendrocyte progenitor cells
type: CreativeWork
description: The store-operated calcium entry (SOCE) pathway is an important route for generating cytosolic Ca2+ signals that regulate a diverse array of biological processes. Abnormal SOCE seem to underlie several diseases that notably include allergy, inflammation, acute pancreatitis and cancer. Therefore, any modulator of this pathway is likely to have significant impact in cell biology under both normal and abnormal conditions. In this study, the FDA-approved drug library was screened for agents that share significant similarity in 3D shape and surface electrostatics with few, hitherto best-known inhibitors of SOCE. This has led to the identification of five drugs that showed dose- dependent inhibition of SOCE in cell-based assay, probably through blocking SOCE pathway extracellularly. Of these drugs, leflunomide and teriflunomide could suppress SOCE significantly at clinically-relevant doses and this provides for an additional mechanism towards the therapeutic utility of these drugs as immunosuppressants. Few more compounds from each of the 4 different pharmacological classes were further tested using cell-based methods to find agents with more potent SOCE-inhibitory potency. Three candidates with better potency namely trequinsin, roflumilast N-oxide and vidofludimus, were identified. Of these compounds, vidofludimus which is known to be an inhibitor of the dihydroorotate dehydrogenase (DHODH) enzyme, proved to be the most potent (IC50~1.4μM) SOCE inhibitor among all the drugs tested, inhibitor of SOCE as it could suppress SOCE significantly at nanomolar dose. Next, selected drugs identified with SOCE suppressive ability were evaluated against the proliferation of different lung cancer cells namely H520, H1752, and LK2. In agreement with previous studies with bona fide SOCE inhibitors, the chosen drugs significantly reduced proliferation of those lung cancer cells. Interestingly, the anti-proliferative activity of most of the selected drugs were observed at concentrations a…
abstract: The store-operated calcium entry (SOCE) pathway is an important route for generating cytosolic Ca2+ signals that regulate a diverse array of biological processes. Abnormal SOCE seem to underlie several diseases that notably include allergy, inflammation, acute pancreatitis and cancer. Therefore, any modulator of this pathway is likely to have significant impact in cell biology under both normal and abnormal conditions. In this study, the FDA-approved drug library was screened for agents that share significant similarity in 3D shape and surface electrostatics with few, hitherto best-known inhibitors of SOCE. This has led to the identification of five drugs that showed dose- dependent inhibition of SOCE in cell-based assay, probably through blocking SOCE pathway extracellularly. Of these drugs, leflunomide and teriflunomide could suppress SOCE significantly at clinically-relevant doses and this provides for an additional mechanism towards the therapeutic utility of these drugs as immunosuppressants. Few more compounds from each of the 4 different pharmacological classes were further tested using cell-based methods to find agents with more potent SOCE-inhibitory potency. Three candidates with better potency namely trequinsin, roflumilast N-oxide and vidofludimus, were identified. Of these compounds, vidofludimus which is known to be an inhibitor of the dihydroorotate dehydrogenase (DHODH) enzyme, proved to be the most potent (IC50~1.4μM) SOCE inhibitor among all the drugs tested, inhibitor of SOCE as it could suppress SOCE significantly at nanomolar dose. Next, selected drugs identified with SOCE suppressive ability were evaluated against the proliferation of different lung cancer cells namely H520, H1752, and LK2. In agreement with previous studies with bona fide SOCE inhibitors, the chosen drugs significantly reduced proliferation of those lung cancer cells. Interestingly, the anti-proliferative activity of most of the selected drugs were observed at concentrations a…
author: Rahman, Md Saifur
language: en
keywords: Store operated calcium entry, SOCE blockers, Drug repurposing, OPCs, OPCS differentiation, multiple sclerosis, SOCE in OPCs
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/7347ab86-c060-4d7e-8aee-aee114c38eb7/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2020-04-07
date modified: 2026-07-22T22:24:23Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.51956