Identification of pyrazolopyridazinones as PDEδ inhibitors

• DOI: 10.1038/ncomms11360
• Publication Date: 2016-04-20T11:14:29Z
• Authors: 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-F...; Alaa Al Saabi; Matthias Baumann; Peter Nussbaumer; Alfred Wittinghofer; Herbert Waldmann; Philippe I.H. Bas...
• Keywords: Phosphodiesterase Inhibitors; Science; Gene Expression; Antineoplastic Agents; Crystallography, X-Ray; Article; Protein Structure, Secondary; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; Cell Line, Tumor; Humans; Protein Interaction Domains and Motifs; Cyclic Nucleotide Phosphodiesterases, Type 6; 0303 health sciences; Binding Sites; Q; Pancreatic Ducts; Epithelial Cells; Recombinant Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Molecular Docking Simulation; Pyrazines; Pyrazoles; Benzimidazoles; Protein Binding

AbstractThe 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.