Identification of pyrazolopyridazinones as PDEδ inhibitors.
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.
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Björn
B
Papke
Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Sandip
S
Murarka
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Holger A
HA
Vogel
Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Pablo
P
Martín-Gago
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Marija
M
Kovacevic
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Dina C
DC
Truxius
Structural Biology Group, Max Planck Institute for Molecular Physiology, D-44227 Dortmund, Germany.
Eyad K
EK
Fansa
Structural Biology Group, Max Planck Institute for Molecular Physiology, D-44227 Dortmund, Germany.|Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, UK.
Shehab
S
Ismail
Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Gunther
G
Zimmermann
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.
Kaatje
K
Heinelt
Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
Carsten
C
Schultz-Fademrecht
Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
Alaa
A
Al Saabi
Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
Matthias
M
Baumann
Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
Peter
http://orcid.org/0000-0002-2761-629X
P
Nussbaumer
Structural Biology Group, Max Planck Institute for Molecular Physiology, D-44227 Dortmund, Germany.
Alfred
A
Wittinghofer
Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.|TU Dortmund, Faculty of Chemistry and Chemical Biology, D-44227 Dortmund, Germany.
Herbert
H
Waldmann
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.|TU Dortmund, Faculty of Chemistry and Chemical Biology, D-44227 Dortmund, Germany.
Philippe I H
PI
Bastiaens
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D062105:Molecular Docking Simulation; D010183:Pancreatic Ducts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D001562:Benzimidazoles; C117307:KRAS protein, human; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; C581772:deltarasin; C000610411:deltazinone 1; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D016283:Proto-Oncogene Proteins p21(ras)