Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gαq/11-Mediated Signaling Pathways,ACS Pharmacology & Translational Science

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Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gαq/11-Mediated Signaling Pathways
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2023-11-10 , DOI: 10.1021/acsptsci.3c00214
Jan Hendrik Voss ₁

Affiliation

The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are natural products, which inhibit heterotrimeric Gα_q/11 proteins with high potency and outstanding selectivity. Historically, pharmacological modulation of Gα proteins was only achieved by treatment with pertussis toxin and cholera toxin, whose application can be tedious and is restricted to the inhibition of Gα_i/o proteins and activation of Gα_s proteins, respectively. The breakthrough discovery and characterization of YM and FR rendered the closely related Gα_q, Gα₁₁, and Gα₁₄ proteins amenable to pharmacological inhibition, and since then, both compounds have become widely used in molecular pharmacology and were also proven to be efficacious in animal models of disease. In the past years, both YM and FR were thoroughly characterized and have substantially contributed to an improved understanding of Gα_q/11 signaling on a molecular and cellular level. Yet, the possibilities to interrogate Gα_q/11 signaling in complex systems have only been exploited in a very limited number of studies, whose promising initial results warrant further application of YM and FR in basic and translational research. As both compounds have become commercially available as of late, this review focuses on their application in cell-based assays and in vivo systems, highlighting their qualities as tool compounds and providing instructions for their use.

中文翻译：

推荐的工具化合物：YM-254890 和 FR900359 在研究 Gαq/11 介导的信号通路中的应用

大环解肽 YM-254890 （YM）和 FR900359 （FR）是天然产物，可抑制异源三聚体 Gα_q/11 蛋白，具有高效效力和出色的选择性。从历史上看，Gα 蛋白的药理学调节只能通过百日咳毒素和霍乱毒素处理来实现，其应用可能很乏味，并且分别仅限于抑制 Gα_i/o 蛋白和 Gα_s 蛋白的激活。YM 和 FR 的突破性发现和表征使密切相关的 Gα_q、Gα₁₁ 和 Gα₁₄ 蛋白容易受到药理学抑制，从那时起，这两种化合物已广泛用于分子药理学，并且在疾病的动物模型中也被证明是有效的。在过去的几年中，YM 和 FR 都得到了彻底的表征，并为在分子和细胞水平上提高对 Gα_q/11 信号转导的理解做出了重大贡献。然而，在复杂系统中询问 Gα_q/11 信号转导的可能性仅在非常有限的研究中得到利用，其有希望的初步结果保证了 YM 和 FR 在基础和转化研究中的进一步应用。由于这两种化合物最近已上市，因此本文重点介绍它们在基于细胞的测定和体内系统中的应用，重点介绍它们作为工具化合物的品质并为其使用说明。

更新日期：2023-11-10

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