2. Academic Validation
  3. Identification of pyrazolopyridazinones as PDEδ inhibitors

Identification of pyrazolopyridazinones as PDEδ inhibitors

  • Nat Commun. 2016 Apr 20;7:11360. doi: 10.1038/ncomms11360.
Björn Papke 1,  Sandip Murarka 2,  Holger A Vogel 1,  Pablo Martín-Gago 2,  Marija Kovacevic 1,  Dina C Truxius 1,  Eyad K Fansa 3,  Shehab Ismail 3 4,  Gunther Zimmermann 2,  Kaatje Heinelt 1,  Carsten Schultz-Fademrecht 5,  Alaa Al Saabi 5,  Matthias Baumann 5,  Peter Nussbaumer 5,  Alfred Wittinghofer 3,  Herbert Waldmann 2 6,  Philippe I H Bastiaens 1 6
Affiliations

Affiliations

  • 1 Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
  • 2 Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
  • 3 Structural Biology Group, Max Planck Institute for Molecular Physiology, D-44227 Dortmund, Germany.
  • 4 Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, UK.
  • 5 Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
  • 6 TU Dortmund, Faculty of Chemistry and Chemical Biology, D-44227 Dortmund, Germany.
PMID: 27094677 DOI: 10.1038/ncomms11360
Abstract

The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEδ, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEδ with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEδ inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEδ knockdown in a set of human pancreatic Cancer cell lines.

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