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SUMMARY:Selective chemical intervention on protein-protein interactions: f
 rom inhibitors to degraders
DTSTART:20171017T161500
DTEND:20171017T180000
DTSTAMP:20260314T211031Z
UID:1fc446f3e2d70456de05fb0040f515930c79ec9d2c30d7f7c31c939e
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Alessio Ciulli\, University of Dundee\nTargeting protein
 -protein interactions (PPIs) is a frontier goal of chemical intervention i
 nto biology\, and provides attractive new targets for drug discovery. Find
 ing high-quality small molecules targeting PPI sites is\, however\, a chal
 lenging task\, and even more so achieving single-target selectivity\, espe
 cially when the target shares homologous functional domains and highly con
 served binding sites with neighboring proteins.\n \nOur lab has developed
  and applied chemical biology approaches\, leveraging rational structure-d
 riven medicinal chemistry\, to help to address these challenges. Represent
 ative examples of our approaches will be illustrated:\n1) structure-guided
  fragment-based design of VH298\, a potent\, selective and on-target inhib
 itor of the von Hippel-Lindau (VHL) E3 ubiquitin ligase\, providing a nove
 l chemical probe for hypoxia signaling pathway [1\,2]\;\n2) development of
  a chemical genetic approach to allele-selective inhibition of BET bromodo
 main proteins Brd2\, Brd3\, Brd4 and BrdT\, starting from pan-selective in
 hibitors such as JQ1 / I-BET762 [3]\;\n3) how we have combined the two inh
 ibitors to design bivalent chemical degraders\, also known as PROTACs\, wh
 ich led to the discovery of MZ1\, a potent and selective VHL-based degrade
 r of the BET protein Brd4 [4]. Structural insights into PROTAC-induced PPI
 s between ligase and bromodomain has shone new light into cooperative mole
 cular recognition of bivalent degraders for selective protein degradation\
 , and informed the structure-guided design of highly preferential Brd4 deg
 raders [5].\n \nOur work has revealed new selective chemical tools to pro
 be biology (available at the Chemical Probes Portal\, www.chemicalprobes.o
 rg) and unveiled deeper understanding of how PROTACs work that is impactin
 g their translation from mere chemical tools to future molecular therapeut
 ics.
LOCATION:BCH 2218 https://plan.epfl.ch/?room==BCH%202218
STATUS:CONFIRMED
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