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A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2
P. Martín-Gago, E.K. Fansa, C.H. Klein, , P. Janning, M. Schürmann, M. Metz, S. Ismail, C. Schultz-Fademrecht, M. BaumannShow More
Published in Wiley-VCH Verlag
PMID: 28106325
Volume: 56
Issue: 9
Pages: 2423 - 2428
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 nm), interference with Ras signaling and growth inhibition require 5–20 μm 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. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
About the journal
JournalData powered by TypesetAngewandte Chemie - International Edition
PublisherData powered by TypesetWiley-VCH Verlag