Structure guided design and kinetic analysis of highly potent benzimidazole inhibitors targeting the pdeδ Prenyl binding site

Zimmermann, G., Schultz-Fademrecht, C., Küchler, P., Murarka, S., Ismail, S. , Triola, G., Nussbaumer, P., Wittinghofer, A. and Waldmann, H. (2014) Structure guided design and kinetic analysis of highly potent benzimidazole inhibitors targeting the pdeδ Prenyl binding site. Journal of Medicinal Chemistry, 57(12), pp. 5435-5448. (doi: 10.1021/jm500632s) (PMID:24884780)

Abstract

K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras–PDEδ interaction by small molecules impairs Ras localization and signaling. Here we describe in detail the identification and structure guided development of Ras–PDEδ inhibitors targeting the farnesyl binding pocket of PDEδ with nanomolar affinity. We report kinetic data that characterize the binding of the most potent small molecule ligands to PDEδ and prove their binding to endogenous PDEδ in cell lysates. The PDEδ inhibitors provide promising starting points for the establishment of new drug discovery programs aimed at cancers harboring oncogenic K-Ras.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ismail, Dr Shehab
• Authors: Zimmermann, G., Schultz-Fademrecht, C., Küchler, P., Murarka, S., Ismail, S., Triola, G., Nussbaumer, P., Wittinghofer, A., and Waldmann, H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804