Targeting guanine nucleotide exchange factors for novel cancer drug discovery.

IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-17 DOI:10.1080/17460441.2024.2368242
Sahar F Bannoura, Husain Yar Khan, Md Hafiz Uddin, Ramzi M Mohammad, Boris C Pasche, Asfar S Azmi
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Abstract

Introduction: Guanine nucleotide exchange factors (GEFs) regulate the activation of small GTPases (G proteins) of the Ras superfamily proteins controlling cellular functions. Ras superfamily proteins act as 'molecular switches' that are turned 'ON' by guanine exchange. There are five major groups of Ras family GTPases: Ras, Ran, Rho, Rab and Arf, with a variety of different GEFs regulating their GTP loading. GEFs have been implicated in various diseases including cancer. This makes GEFs attractive targets to modulate signaling networks controlled by small GTPases.

Areas covered: In this review, the roles and mechanisms of GEFs in malignancy are outlined. The mechanism of guanine exchange activity by GEFs on a small GTPase is illustrated. Then, some examples of GEFs that are significant in cancer are presented with a discussion on recent progress in therapeutic targeting efforts using a variety of approaches.

Expert opinion: Recently, GEFs have emerged as potential therapeutic targets for novel cancer drug development. Targeting small GTPases is challenging; thus, targeting their activation by GEFs is a promising strategy. Most GEF-targeted drugs are still in preclinical development. A deeper biological understanding of the underlying mechanisms of GEF activity and utilizing advanced technology are necessary to enhance drug discovery for GEFs in cancer.

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以鸟嘌呤核苷酸交换因子为靶点,发现新型抗癌药物。
引言鸟嘌呤核苷酸交换因子(GEF)调节控制细胞功能的 Ras 超家族蛋白的小 GTP 酶(G 蛋白)的活化。Ras 超家族蛋白就像 "分子开关",通过鸟嘌呤交换打开 "开关"。Ras 家族 GTPases 有五大类:Ras、Ran、Rho、Rab 和 Arf,它们的 GTP 负载由多种不同的 GEFs 调节。GEF 与包括癌症在内的多种疾病有关。这使得 GEFs 成为调节由小 GTP 酶控制的信号网络的有吸引力的目标:本综述概述了 GEFs 在恶性肿瘤中的作用和机制。本综述概述了GEFs在恶性肿瘤中的作用和机制,并说明了GEFs对小GTP酶进行鸟嘌呤交换活动的机制。然后,举例说明了在癌症中具有重要作用的 GEFs,并讨论了利用各种方法进行靶向治疗的最新进展:最近,GEFs 已成为新型抗癌药物开发的潜在治疗靶点。以小 GTP 酶为靶点具有挑战性;因此,以 GEFs 激活小 GTP 酶为靶点是一种很有前景的策略。大多数以 GEF 为靶点的药物仍处于临床前开发阶段。有必要从生物学角度深入了解 GEF 活性的基本机制,并利用先进的技术来促进癌症 GEF 药物的开发。
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来源期刊
CiteScore
10.20
自引率
1.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Drug Discovery (ISSN 1746-0441 [print], 1746-045X [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on novel technologies involved in the drug discovery process, leading to new leads and reduced attrition rates. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering chemoinformatics; bioinformatics; assay development; novel screening technologies; in vitro/in vivo models; structure-based drug design; systems biology Drug Case Histories examining the steps involved in the preclinical and clinical development of a particular drug The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and other closely related professionals looking to enhance the success of their drug candidates through optimisation at the preclinical level.
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