Identification of pyrazolopyridazinones as PDEδ inhibitors

Björn Papke, Sandip Murarka, Holger A Vogel, Pablo Martín-Gago, Marija Kovacevic, Dina C Truxius, Eyad K Fansa, Shehab Ismail, Gunther Zimmermann, Kaatje Heinelt, Carsten Schultz-Fademrecht, Alaa Al Saabi, Matthias Baumann, Peter Nussbaumer, Alfred Wittinghofer, Herbert Waldmann () and Philippe I.H. Bastiaens ()
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Björn Papke: Max Planck Institute of Molecular Physiology
Sandip Murarka: Max Planck Institute of Molecular Physiology
Holger A Vogel: Max Planck Institute of Molecular Physiology
Pablo Martín-Gago: Max Planck Institute of Molecular Physiology
Marija Kovacevic: Max Planck Institute of Molecular Physiology
Dina C Truxius: Max Planck Institute of Molecular Physiology
Eyad K Fansa: Structural Biology Group, Max Planck Institute for Molecular Physiology
Shehab Ismail: Structural Biology Group, Max Planck Institute for Molecular Physiology
Gunther Zimmermann: Max Planck Institute of Molecular Physiology
Kaatje Heinelt: Max Planck Institute of Molecular Physiology
Carsten Schultz-Fademrecht: Lead Discovery Center GmbH
Alaa Al Saabi: Lead Discovery Center GmbH
Matthias Baumann: Lead Discovery Center GmbH
Peter Nussbaumer: Lead Discovery Center GmbH
Alfred Wittinghofer: Structural Biology Group, Max Planck Institute for Molecular Physiology
Herbert Waldmann: Max Planck Institute of Molecular Physiology
Philippe I.H. Bastiaens: Max Planck Institute of Molecular Physiology

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11360

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