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- Title
A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2.
- Authors
Martín ‐ Gago, Pablo; Fansa, Eyad K.; Klein, Christian H.; Murarka, Sandip; Janning, Petra; Schürmann, Marc; Metz , Malte; Ismail, Shehab; Schultz ‐ Fademrecht, Carsten; Baumann, Matthias; Bastiaens, Philippe I. H.; Wittinghofer, Alfred; Waldmann, Herbert
- Abstract
Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro ( KD<10 n m), interference with Ras signaling and growth inhibition require 5-20 μ m compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and -dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas-PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas.
- Subjects
HYDROGEN bonding; MOLECULAR chaperones; RAS proteins; GROWTH factors; C-terminal binding proteins; CARBONYL group
- Publication
Angewandte Chemie, 2017, Vol 129, Issue 9, p2463
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201610957