Novotny Chris J, Hamilton Gregory L, McCormick Frank, Shokat Kevan M
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.
ACS Chem Biol. 2017 Jul 21;12(7):1956-1962. doi: 10.1021/acschembio.7b00374. Epub 2017 Jun 19.
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.
突变激活的Ras是在所有恶性肿瘤中发现的最常见的致癌驱动因素之一，其选择性抑制长期以来一直是制药和学术界的目标。抑制过度活跃的Ras信号传导的最古老且最有效的方法之一是干扰其翻译后加工及随后的细胞定位。以往针对Ras加工的靶向尝试导致了法尼基转移酶抑制剂的开发，该抑制剂可抑制H-Ras的定位，但不能抑制K-Ras，因为K-Ras能够通过香叶基香叶基转移酶的替代异戊二烯化绕过法尼基转移酶抑制作用。在此，我们展示了一种法尼基转移酶新底物的创建，该底物可防止香叶基香叶基转移酶的替代异戊二烯化，并使致癌性K-Ras在细胞中错误定位。
