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Title: Drug repurposing against the store-operated calcium entry (SOCE) pathway and subsequent exploration of SOCE in oligodendrocyte progenitor cells
Author: Rahman, Md Saifur
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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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 at which they could significantly inhibit SOCE identified in those lung cancer cells. Although the possible contribution of the inhibition of the known targets of these drugs towards their anti-proliferative activity could not be ruled out, it was nevertheless indicative of the fact that their SOCE-inhibitory property was definitely implicated. This, in agreement with existing literature, hinted towards the fact that SOCE can be targeted to achieve potential therapeutic benefit against lung cancer and other cancer cells of epithelial origins. Of the drugs identified at the early phase of the present work to possess SOCE suppressive ability, teriflunomide is approved for multiple sclerosis (MS) which is believed to be autoimmune origin. The pro-drug of teriflunomide is leflunomide which is approved for managing rheumatoid arthritis. Since oligodendrocytes progenitor cells (OPCs) play important role in MS due to their myelin forming ability upon differentiation, SOCE was characterized in OPCs using single cell Ca2+ imaging approach and effect of some SOCE inhibitory compounds were then evaluated for any role in OPC differentiation. Employing different biochemical and imaging methods, AnCoA4, a known SOCE blocker was found to promote differentiation of OPCs. This finding could help to identify new target to develop therapeutic for demyelinating diseases like MS.
Supervisor: Rahman, Taufiq Sponsor: Cambridge Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.805883  DOI:
Keywords: Store operated calcium entry ; SOCE blockers ; Drug repurposing ; OPCs ; OPCS differentiation ; multiple sclerosis ; SOCE in OPCs
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