Repurposing Known Drugs as Inhibitors of the Store-Operated Calcium Entry Pathway

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• Saifur Rahman – Graduate Student, Pharmacology, Wolfson College
• Friday 04 March 2016, 15:30-15:40
• Lee Hall, Wolfson College.

If you have a question about this talk, please contact Francisco Orozco.

Store-operated calcium entry (SOCE) pathway, which is activated following physiological (e.g. by the Ca2+ -mobilizing second messenger, IP3 ) or pharmacological (e.g. by thapsigargin, an inhibitor of the sarco-endoplasmic reticulum Ca2+ -ATPase or SERCA pump) depletion of internal Ca2+ stores, is a prominent contributor towards generation of cytosolic Ca2+ signals. Ca2+ influx via SOCE helps in refilling the emptied stores in non-excitable cells but can also regulate specific downstream cellular processes including gene transcription, secretion and metabolism. In recent years, several human diseases have been linked to abnormal SOCE , including allergy, inflammatory bowel disease, thrombosis and some forms of cancer. Drugs targeting this pathway could therefore be of considerable clinical benefit. In recent time, drug repositioning or re-purposing has drawn considerable attention worldwide as it offers the likelihood of identifying potential lead scaffolds from the existing drugs that are already well characterized, especially from the toxicological and pharmacokinetic point of view. Using few well-known SOCE inhibitors, the conformers of all existing drugs were screened in silico to identify molecules possessing considerable similarities in 3D shape and electrostatics with the baits. After manual inspections from the top hits of each screening for scaffold diversity, eight different drugs were chosen for bioassay. The latter involved single cell Ca2+ imaging using Fura-2 with SOCE triggered by IP3 -mediated store emptying as well as thapsigarginevoked SERCA inhibition. Of the 8 drugs, five of them, namely Leflunomide, Teriflunomide, Tolvaptan, Nifuroxazide and Omeprazole, substantially blocked SOCE in SHSY -5Y neuroblastoma cells and rat basophilic leukemia (RBL-1) cells. Upon prolonged incubation, Leflunomide and Teriflunomide showed significant SOCE inhibition. Thus, the chemical scaffolds of these drugs can potentially be explored further for future development of effective SOCE inhibitors. The study also reveals possible off target effects of these drugs.

This talk is part of the Wolfson Research Event 2016 series.

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• Lee Hall, Wolfson College
• Wolfson Research Event 2016

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