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Publication Abstract from PubMed

Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6delta 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 mum compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6delta by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6delta 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-PDE6delta interaction may impair the growth of tumors driven by oncogenic KRas.

A PDE6delta-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2.,Martin-Gago P, Fansa EK, Klein CH, Murarka S, Janning P, Schurmann M, Metz M, Ismail S, Schultz-Fademrecht C, Baumann M, Bastiaens PI, Wittinghofer A, Waldmann H Angew Chem Int Ed Engl. 2017 Jan 20. doi: 10.1002/anie.201610957. PMID:28106325^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.