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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. [ABSTRACT FROM AUTHOR]

A new type of allosteric inhibition by small molecules is proposed that should be applicable to all proteins involved intrinsically in protein–protein interactions. It is based on targeting their rare interaction states that can be detected by high‐pressure NMR spectroscopy (see picture). An example is the Ras‐protein where the protein–protein interaction of Ras with effectors can be modulated by small compounds that bind to the conformational states 1(T) or 1(0). [ABSTRACT FROM AUTHOR]