BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Talks.cam//talks.cam.ac.uk//
X-WR-CALNAME:Talks.cam
BEGIN:VEVENT
SUMMARY:Repurposing Known Drugs as Inhibitors of the Store-Operated Calciu
 m Entry Pathway - Saifur Rahman – Graduate Student\, Pharmacology\, Wolf
 son College
DTSTART:20160304T153000Z
DTEND:20160304T154000Z
UID:TALK64991@talks.cam.ac.uk
CONTACT:Francisco Orozco
DESCRIPTION:Store-operated calcium entry (SOCE) pathway\, which is activat
 ed following physiological (e.g. by the Ca2+ -mobilizing second messenger\
 , IP3) or pharmacological (e.g. by thapsigargin\, an inhibitor of the sarc
 o-endoplasmic reticulum Ca2+ -ATPase or SERCA pump) depletion of internal 
 Ca2+ stores\, is a prominent contributor towards generation of cytosolic C
 a2+ signals. Ca2+ influx via SOCE helps in refilling the emptied stores in
  non-excitable cells but can also regulate specific downstream cellular pr
 ocesses including gene transcription\, secretion and metabolism. In recent
  years\, several human diseases have been linked to abnormal SOCE\, includ
 ing allergy\, inflammatory bowel disease\, thrombosis and some forms of ca
 ncer. Drugs targeting this pathway could therefore be of considerable clin
 ical benefit. In recent time\, drug repositioning or re-purposing has draw
 n considerable attention worldwide as it offers the likelihood of identify
 ing potential lead scaffolds from the existing drugs that are already well
  characterized\, especially from the toxicological and pharmacokinetic poi
 nt of view. Using few well-known SOCE inhibitors\, the conformers of all e
 xisting drugs were screened in silico to identify molecules possessing con
 siderable similarities in 3D shape and electrostatics with the baits. Afte
 r manual inspections from the top hits of each screening for scaffold dive
 rsity\, eight different drugs were chosen for bioassay. The latter involve
 d single cell Ca2+ imaging using Fura-2 with SOCE triggered by IP3-mediate
 d store emptying as well as thapsigarginevoked SERCA inhibition. Of the 8 
 drugs\, five of them\, namely Leflunomide\, Teriflunomide\, Tolvaptan\, Ni
 furoxazide and Omeprazole\, substantially blocked SOCE in SHSY-5Y neurobla
 stoma cells and rat basophilic leukemia (RBL-1) cells. Upon prolonged incu
 bation\, 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 als
 o reveals possible off target effects of these drugs.
LOCATION:Lee Hall\, Wolfson College
END:VEVENT
END:VCALENDAR