文章：

癌症中的蛋白质脂化：机制、失调和新出现的药物靶点

Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets

原文发布日期：2024-02-29

DOI: 10.1038/s41568-024-00666-x

类型: Review Article

开放获取: 否

英文摘要：

Protein lipidation describes a diverse class of post-translational modifications (PTMs) that is regulated by over 40 enzymes, targeting more than 1,000 substrates at over 3,000 sites. Lipidated proteins include more than 150 oncoproteins, including mediators of cancer initiation, progression and immunity, receptor kinases, transcription factors, G protein-coupled receptors and extracellular signalling proteins. Lipidation regulates the physical interactions of its protein substrates with cell membranes, regulating protein signalling and trafficking, and has a key role in metabolism and immunity. Targeting protein lipidation, therefore, offers a unique approach to modulate otherwise undruggable oncoproteins; however, the full spectrum of opportunities to target the dysregulation of these PTMs in cancer remains to be explored. This is attributable in part to the technological challenges of identifying the targets and the roles of protein lipidation. The early stage of drug discovery for many enzymes in the pathway contrasts with efforts for drugging similarly common PTMs such as phosphorylation and acetylation, which are routinely studied and targeted in relevant cancer contexts. Here, we review recent advances in identifying targetable protein lipidation pathways in cancer, the current state-of-the-art in drug discovery, and the status of ongoing clinical trials, which have the potential to deliver novel oncology therapeutics targeting protein lipidation.

摘要翻译： 

蛋白质脂化修饰是一类多样化的翻译后修饰，由40多种酶调控，在3,000多个位点上靶向超过1,000种底物。脂化蛋白包含150多种癌蛋白，涵盖肿瘤发生、进展与免疫的介导因子、受体激酶、转录因子、G蛋白偶联受体及细胞外信号蛋白。脂化修饰通过调控蛋白质底物与细胞膜的物理相互作用，影响信号传导和运输过程，在代谢与免疫中发挥关键作用。因此，靶向蛋白质脂化为调控传统不可成药癌蛋白提供了独特策略，但针对这类翻译后修饰在癌症中失调的全谱靶向机遇仍有待探索。这部分归因于识别脂化靶点及其功能的技术挑战。与磷酸化、乙酰化等已被充分研究并在癌症背景下常规靶向的常见翻译后修饰相比，该通路中多数酶的药物研发尚处于早期阶段。本文综述了癌症中可靶向蛋白脂化通路的最新发现、药物研发的前沿进展及正在进行中的临床试验现状，这些研究有望催生靶向蛋白质脂化的新型肿瘤疗法。

原文链接：

Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets