Lin David Tse Shen, Davis Nicholas G, Conibear Elizabeth
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Department of Pharmacology, Wayne State University, Detroit, MI 48201, U.S.A.
Biochem Soc Trans. 2017 Aug 15;45(4):913-921. doi: 10.1042/BST20160303. Epub 2017 Jun 19.
The Ras proteins are well-known drivers of many cancers and thus represent attractive targets for the development of anticancer therapeutics. Inhibitors that disrupt the association of the Ras proteins with membranes by blocking the addition of the farnesyl lipid moiety to the Ras C-terminus failed in clinical trials. Here, we explore the possibility of targeting a second lipid modification, S-acylation, commonly referred to as palmitoylation, as a strategy to disrupt the membrane interaction of specific Ras isoforms. We review the enzymes involved in adding and removing palmitate from Ras and discuss their potential roles in regulating Ras tumorigenesis. In addition, we examine other proteins that affect Ras protein localization and may serve as future drug targets.
Ras蛋白是许多癌症的著名驱动因子，因此是开发抗癌疗法的有吸引力的靶点。通过阻断法尼基脂质部分添加到Ras C末端来破坏Ras蛋白与膜的结合的抑制剂在临床试验中失败了。在这里，我们探索将靶向第二种脂质修饰——S-酰化（通常称为棕榈酰化）作为破坏特定Ras亚型膜相互作用的策略的可能性。我们回顾了参与Ras添加和去除棕榈酸酯的酶，并讨论了它们在调节Ras肿瘤发生中的潜在作用。此外，我们研究了其他影响Ras蛋白定位并可能作为未来药物靶点的蛋白质。
