Tuesday, June 20, 2017

Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K-Ras

Chris J. Novotny, Gregory L. Hamilton, Frank McCormick, and Kevan M. Shokat
† Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, United States
‡ NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland 21701, United States
§ Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, United States

ACS Chem. Biol., Article ASAP

DOI: 10.1021/acschembio.7b00374

Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of farnesyltransferase inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition through alternative prenylation by geranylgeranyltransferase. Here, we present the creation of a neo-substrate for farnesyltransferase that prevents the alternative prenlation by geranylgeranyltransferase and mislocalizes oncogenic K-Ras in cells.

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

Felix M. Paulussen, Gina K. Schouten, Carolin Moertl, Jolanda Verheul, Irma Hoekstra, Gregory M. Koningstein, George H. Hutchins, Aslihan Al...