Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K-Ras,ACS Chemical Biology

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Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K-Ras
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-06-19 00:00:00 , DOI: 10.1021/acschembio.7b00374
Chris J. Novotny ₁ , Gregory L. Hamilton ₁ , Frank McCormick _{2,

3} , Kevan M. Shokat ₁

Affiliation

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.

中文翻译：

法尼基转移酶介导的共价抑制剂的传递克服了替代的异戊烯化作用以使K-Ras错位

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药学和学术界的目标。抑制过度活跃的Ras信号传导的最古老，最有效的方法之一是干扰其翻译后加工和随后的细胞定位。先前针对Ras加工的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定位，但不能抑制K-Ras，因为它能够通过香叶基香叶基转移酶通过交替的烯丙基化作用来绕过法尼基转移酶抑制作用。在这里，我们介绍了法尼基转移酶的新底物的创建，该新底物可防止由香叶基香叶基转移酶进行的替代预配基作用，并在细胞中错误定位致癌的K-Ras。

更新日期：2017-06-28

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