Martín-Gago, P. et al. (2017) A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2. Angewandte Chemie (International Edition), 56(9), pp. 2423-2428. (doi: 10.1002/anie.201610957) (PMID:28106325)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This research was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich SFB 642 to A.W., H.W., and P.I.H.B.), the Deutsche Krebshilfe (Grant 110995 to P.I.H.B.), and the European Research Council under the European Union's Seventh Framework Program (FP7/2007–2013; ERC Grant 322637 to P.I.H.B., ERC Grant 268309 to H.W. and ERC Grant 268782 to A.W.) |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Ismail, Dr Shehab |
| Authors: | Martín-Gago, P., Fansa, E. K., Klein, C. H., Murarka, S., Janning, P., Schürmann, M., Metz, M., Ismail, S., Schultz-Fademrecht, C., Baumann, M., Bastiaens, P. I.H., Wittinghofer, A., and Waldmann, H. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Angewandte Chemie (International Edition) |
| Publisher: | Wiley |
| ISSN: | 1433-7851 |
| ISSN (Online): | 1521-3773 |
| Published Online: | 20 January 2017 |
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