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SUMMARY:Designing drugs on an intrinsically disordered protein involved in
  pancreatic cancer - Jose L Neira Instituto de Biologia Molecular y Celula
 r. Universidad Miguel Hernandez\, Elche (Alicante) Spain
DTSTART:20160824T093000Z
DTEND:20160824T103000Z
UID:TALK67124@talks.cam.ac.uk
CONTACT:Jerome Charmet
DESCRIPTION:Intrinsically disordered proteins (IDPs) are prevalent in euka
 ryotes\, performing signaling and regulatory functions. Often associated w
 ith human diseases\, they constitute drug-design targets. NUPR1 (or p8) is
  a multifunctional IDP\, over-expressed and involved in pancreatic ductal 
 adenocarcinoma (PDAC) development. In this seminar\, we follow a three-par
 t strategy. First\, we show how p8 is an IDP\, from an experimental and th
 eoretical (primary structure) point of view. Second\, we describe the inte
 ractions with its three natural partners and how the complexes formed are 
 “fuzzy”. Finally\, we describe our attempts to design drugs against p8
 \, based on those partners. In a first attempt\, by screening 1120 FDA-app
 roved compounds\, fifteen candidates were selected\, and their interaction
 s with NUPR1 were characterized by experimental and simulation techniques.
  The protein remained disordered upon binding to all fifteen candidates. T
 hese compounds were tested in PDAC-derived cell-based assays\, and all ind
 uced cell-growth arrest and senescence\, reduced cell migration\, and decr
 eased chemoresistance\, mimicking NUPR1-deficiency. The most effective com
 pound completely arrested tumor development in vivo on xenografted PDAC-de
 rived cells in mice. In a second attempt\, we carried out “hypothesis-dr
 iven” experiments to identify other compounds against p8 (peptides and d
 endrimers). Besides reporting the discovery of a compound targeting an int
 act IDP and specifically active against PDAC\, our studies prove the possi
 bility to target the ‘fuzzy’ interface of a protein that remains disor
 dered upon binding to its natural biological partners or to selected drugs
 .
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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