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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
Author(s) -
MartínGago Pablo,
Fansa Eyad K.,
Klein Christian H.,
Murarka Sandip,
Janning Petra,
Schürmann Marc,
Metz Malte,
Ismail Shehab,
SchultzFademrecht Carsten,
Baumann Matthias,
Bastiaens Philippe I. H.,
Wittinghofer Alfred,
Waldmann Herbert
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201610957
Subject(s) - kras , chemistry , in vitro , small molecule , microbiology and biotechnology , biochemistry , cancer research , mutation , biology , gene
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 ( K D <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.