Identification of pyrazolopyridazinones as PDEδ inhibitors

Papke, B. et al. (2016) Identification of pyrazolopyridazinones as PDEδ inhibitors. Nature Communications, 7, 11360. (doi: 10.1038/ncomms11360) (PMID:27094677) (PMCID:PMC4843002)

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.

• Item Type: Articles
• Additional Information: This research was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich SFB 642) and the European Research Council under the European Union’s Seventh Framework Program (FP7/2007-2013; ERC Grant 322637 to P.I.H.B., ERC Grant 268309 to H.W. and ERC Grant 268782 to A.W.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ismail, Dr Shehab
• Authors: Papke, B., Murarka, S., Vogel, H. A., Martín-Gago, P., Kovacevic, M., Truxius, D. C., Fansa, E. K., Ismail, S., Zimmermann, G., Heinelt, K., Schultz-Fademrecht, C., Al Saabi, A., Baumann, M., Nussbaumer, P., Wittinghofer, A., Waldmann, H., and Bastiaens, P. I.H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Nature Communications 7:11360
• Publisher Policy: Reproduced under a Creative Commons License