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SUMMARY:Designing drugs on an intrinsically disordered protein involved in
  pancreatic cancer - Professor José Luis Neira\, Instituto de Biologia Mo
 lecular y Celular\, Universidad Miguel Hernández\, Elche (Alicante)\, Spa
 in
DTSTART:20170705T093000Z
DTEND:20170705T103000Z
UID:TALK72898@talks.cam.ac.uk
CONTACT:23027
DESCRIPTION:Intrinsically disordered proteins (IDPs) are prevalent in euka
 ryotes. They are often associated with human diseases\, and they constitut
 e drug-design targets. NUPR1 (or p8) is a multifunctional IDP\, over-expre
 ssed and involved in human pancreatic ductal adenocarcinoma (PDAC) develop
 ment. In the last ten years we have been studying its conformational prope
 nsities and its interaction with other biomolecules. P8 binds DNA\, but it
  does not acquire a folded structure upon binding\; in contrast\, its phop
 horylated form acquires more structure in the presence of DNA\, but the st
 ructure is not rigid. The protein also binds to: (i) prothymosin alpha\, h
 elping in controlling apoptosis\; and (i) the male specific lethal protein
  (MSL1)\, helping in DNA-repair\, with\, in both cases\, low-micromolar af
 finity. In both cases\, the p8-protein complexes are “fuzzy” (disorder
 ed). By screening a 1200-compound FDA-approved library\, fifteen candidate
 s have been selected\, and their interactions with p8 have been characteri
 zed by experimental (fluorescence\, isothermal titration calorimetry (ITC)
  and NMR) and simulation techniques to provide structural models of the p8
 -drug complexes. Upon binding of the drug\, p8 remained disordered. These 
 compounds were tested in PDAC-derived cell-based assays\, and induced cell
 -growth arrest and senescence\, reduced cell migration\, and decreased che
 moresistance\, mimicking NUPR1-deficiency. The most effective compound com
 pletely arrested tumor development in vivo on xenografted PDAC-derived cel
 ls in mice. Thus\, we have been able to describe first occurrence of drug 
 design versus an intact IDP\, proving the possibility to target the interf
 ace of an IDP that remains disordered upon binding to its natural partners
 . We have also started to explore the binding of p8 to other molecules (na
 mely dendrimers and peptides) and we have found out that the binding regio
 n is the same as that of the organic compounds\, which hamper development 
 of PDAC.
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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