A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2
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- 作者：Dr. Pablo Martí ; n-Gago ; Dr. Eyad K. Fansa ; Christian H. Klein ; Dr. Sandip Murarka ; Dr. Petra Janning ; Dr. Marc Schü ; rmann ; Malte Metz &ensp ; Dr. Shehab Ismail ; Dr. Carsten Schultz-Fademrecht ; Dr. Matthias Baumann ; Prof. Dr. Philippe I. H. Bastiaens ; Prof. Dr. Alfred Wittinghofer and Prof. Dr. Herbert Waldmann
- 刊名：Angewandte Chemie International Edition
- 出版年：2017
- 出版时间：February 20, 2017
- 年：2017
- 卷：56
- 期：9
- 页码：2423-2428
- 全文大小：4203K
- ISSN：1521-3773
文摘
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.