Identification of pyrazolopyridazinones as PDE? inhibitors.

ABSTRACT: The prenyl-binding protein PDE? 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 PDE?, 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 PDE? with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDE? 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 PDE? knockdown in a set of human pancreatic cancer cell lines.

SUBMITTER: Papke B 

PROVIDER: S-EPMC4843002 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature