ERK1/2抑制的研究进展:从结构和调控的药物化学角度看。

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Vimlendu Kumar Sah, Ankit Kumar Singh, Adarsh Kumar, Vineet Prajapati, Amandeep Singh Kalsi, Habibullah Khalilullah, Mariusz Jaremko, Abdul-Hamid Emwas, Amita Verma, Pradeep Kumar
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引用次数: 0

摘要

丝裂原活化蛋白激酶(MAPK)通路,也称为RAS/RAF/MEK/ERK通路,是参与调节细胞生长、增殖和存活的关键信号级联。该通路的细胞外信号调节激酶(ERK)亚家族于20世纪90年代被发现。ERK家族包括几种亚型——ERK1、ERK2、ERK3、ERK5和erk6,其中ERK1 (MAPK3)和ERK2 (MAPK1)是最具特征的,在MAPK信号传导中发挥核心作用。ERK信号通路(通常称为ERK通路或ERKp)的解除管制与大约40%的人类癌症有关。这篇综述的重点是ERK1/2的结构见解及其在MAPK信号级联中的关键作用。尽管具有临床意义,但尚未有ERK抑制剂获得FDA批准。一些分子,如SCH772984、SCH900353、乌利希替尼(BVD-523)、CC-9003、KO-947、AZD0364、norathyriol和fr180204,目前正处于临床前或临床试验阶段。这篇综述还强调了ERK抑制剂的设计和合成的最新进展,强调了它们的结构独特性和抑制ERK1/2突变形式的潜力。最后,我们讨论了ERK1/2抑制剂作为fda批准的癌症治疗药物的未来发展方向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Advances in ERK1/2 inhibition: a medicinal chemistry perspective on structure and regulation.

The mitogen-activated protein kinase (MAPK) pathway-also known as the RAS/RAF/MEK/ERK pathway-is a critical signalling cascade involved in regulating cell growth, proliferation, and survival. First discovered in the early 1980s, the pathway's extracellular signal-regulated kinase (ERK) subfamily was identified in the 1990s. The ERK family includes several isoforms-ERK1, ERK2, ERK3, ERK5, and ERK6-with ERK1 (MAPK3) and ERK2 (MAPK1) being the most well-characterised and playing central roles in MAPK signalling. Deregulation of ERK signalling (commonly referred to as the ERK pathway or ERKp) has been implicated in approximately 40% of human cancers. This review focuses on the structural insights of ERK1/2 and their critical role in the MAPK signalling cascade. Despite their clinical significance, no ERK inhibitors have yet been approved by the FDA. Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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