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更新于：2025-05-07

AIMP2

更新于：2025-05-07

基本信息

别名

AIMP2、Aminoacyl tRNA synthase complex-interacting multifunctional protein 2、aminoacyl tRNA synthetase complex interacting multifunctional protein 2

+ [6]

简介

Required for assembly and stability of the aminoacyl-tRNA synthase complex (PubMed:19131329). Mediates ubiquitination and degradation of FUBP1, a transcriptional activator of MYC, leading to MYC down-regulation which is required for aveolar type II cell differentiation. Blocks MDM2-mediated ubiquitination and degradation of p53/TP53. Functions as a proapoptotic factor.

关联

项与 AIMP2 相关的药物

BC-DX101

靶点

AIMP2

作用机制

AIMP2基因抑制剂

在研机构

Excubio Pharmaceuticals, Inc.

原研机构

Excubio Pharmaceuticals, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

Bcl-848

靶点

AIMP2

作用机制

AIMP2 inhibitors

在研机构

Dongguk University

原研机构

Dongguk University

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

EMAP II antibody(Allinaire Therapeutics)

靶点

AIMP2

作用机制

AIMP2 inhibitors

在研机构

Allinaire Therapeutics LLC

原研机构

Allinaire Therapeutics LLC

在研适应症

急性肺损伤 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 AIMP2 相关的临床结果

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100 项与 AIMP2 相关的转化医学

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0 项与 AIMP2 相关的专利（医药）

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117

项与 AIMP2 相关的文献（医药）

2025-01-13·Medicinal Chemistry

An Integrative Computational Approach for the Identification of C-Abl Kinase Inhibitors from Anti-Parkinson Plant-Derived Bioactive

Article

作者: Bello, Ridwan Opeyemi ; Kuthi, Najwa Ahmad ; Abdulsalam, Zainab Naeem ; Ashimiyu-Abdusalam, Zainab ; Umar, Haruna Isiyaku ; Kumar, Neeraj ; Victor, Omoboyede ; Bourhia, Mohammed ; Nafidi, Hiba-Allah ; Bin Jardan, Yousef A. ; Aribo, Elizabeth Oluwabunmi

Background:Oxidative stress is strongly linked to neurodegeneration through the activation of c-Abl kinase, which arrests α-synuclein proteolysis by interacting with parkin interacting substrate (PARIS) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). This activation, triggered by ataxia-telangiectasia mutated (ATM) kinase, leads to dopaminergic neuron loss and α-synuclein aggregation, a critical pathophysiological aspect of Parkinson’s disease (PD). To halt PD progression, pharmacological inhibition of c-Abl kinase is essential. Despite three generations of tyrosine kinase inhibitors (TKIs) being explored for PD treatment, they present significant concerns including poor blood-brain barrier penetration, off-target effects, and severe side effects. Notably, there are currently no FDA-approved c-Abl kinase inhibitors in clinical usage for PD treatment, highlighting the urgent need for potent, safe, and cost-effective alternatives.Objective:This study aims to identify potential c-Abl kinase inhibitors from plant-derived compounds with reported anti-Parkinson's potential and their derivatives using molecular docking, molecular dynamics simulations (MDS), and in silico pharmacokinetics and toxicity profiling.Methods:Seventy-eight compounds sourced from literature were docked against c-Abl kinase using Maestro 12.5. The top three hit compounds, along with nilotinib (control drug), were subjected to drug-likeness, ADMET profiling using the AI Drug Lab server and 100 ns MDS using Desmond.Results:Amburoside A, diarylheptanoid MS13, and dimethylaminomethyl-substituted-curcumin showed binding affinities close to nilotinib, with values of -12.615, -12.556, and -11.895 kcal/mol respectively, compared to nilotinib's -16.826 kcal/mol. The three plant-derived compounds exhibited excellent structural stability and favorable ADMET profiles, including optimal blood-brain barrier permeationConclusion:The three hit compounds identified in this study show potential as c-Abl kinase inhibitors. Given the absence of FDA-approved c-Abl kinase inhibitors for PD, these findings are significant as they could contribute new therapeutic options for the treatment and management of PD. However, further in vitro and in vivo experiments are necessary to validate these findings.

2025-01-01·Biomolecules & Therapeutics

The Dual Role of Survival Genes in Neurons and Cancer Cells: a Strategic Clinical Application of DX2 in Neurodegenerative Diseases and Cancer

Review

作者: Baek, Kyunghwa

In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression. Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells. Survival gene DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), was found to be overexpressed in various cancer types. The potential of DX2 inhibitors as an anti-cancer drug arises from its unique ability to interact with various oncoproteins, such as KRAS and HSP70. Meanwhile, AIMP2 has been reported as a multifunctional cell death-inducing gene, and survival gene DX2 directly and indirectly inhibits AIMP2-induced cell death. DX2 plays multifaceted survival roles in degenerating neurons via various signaling pathways, including PARP 1, TRAF2, and p53 pathways. It is noteworthy that genes that were previously classified as oncogenes, such as AKT and XBP1, are now being considered as curative transgenes for targeting neurodegenerative diseases. A strategic direction for clinical application of survival genes in neurodegenerative disease and in cancer is justified.

2024-12-01·Molecular Therapy: Oncology

The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression

Article

作者: Kim, Bae-Hoon ; Hong, Byung-Su ; Kwon, Yonghoon ; Woo, Tae-Gyun ; Shin, Yun-Jeong ; Jeong, Jiwon ; Seo, Hyunghwan ; Oh, Ah-Young ; Park, Bum-Joon ; Kang, So-Mi ; Park, Soyoung ; Park, Hyo-Pin ; Kim, Hye-Ju ; Jang, Hyewon

Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and in vivo lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).

项与 AIMP2 相关的新闻（医药）

2025-01-09

·精准药物

Cell Chem. Biol. |一种新的变构调节剂诱导泛素化降解

AIMP2-DX2（以下简称DX2）是一种氨酰基-tRNA合成酶相互作用多功能蛋白2 （AIMP2）的致癌变异体，可介导与多种癌症相关因子的致瘤相互作用。降低DX2水平可有效抑制肿瘤发生。此前的研究已经发现DX2可以通过Siah1介导的泛素化降解，但相互作用模式不明。近期，韩国科学家Dae Gyu Kim等人在Cell Chemical Biology上发表了一项突破性研究：Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination。该团队发现了一种化合物SDL01，它可以增强DX2与Siah1之间的相互作用，从而促进DX2的泛素依赖性降解，为癌症的治疗提供了新的思路。首先，作者研究了DX2与Siah1的相互作用模式，通过免疫共沉淀和分子动力学（MD）模拟等方法，确定了二者相互作用位点，发现Siah1的SBD - D1和SBD - D2分别与DX2的NFR和GST域结合，且与HSP70结合位点重叠（先前的研究表明，DX2可以被HSP70稳定），这解释了HSP70对DX2免受Siah1介导泛素化的保护机制。 1. SDL01的鉴定和表征设计与筛选：作者首先进行了化合物的设计合成与筛选，合成七种BC - DXI - 04衍生物，结果发现SDL01（3e）抑制DX2活性最强，因此选择其进行研究。作用机制：接着，作者通过一系列的实验发现SDL01以剂量依赖方式降低DX2水平，而不影响AIMP2水平，且在蛋白水平发挥作用；同时SDL01增加了DX2泛素化，诱导DX2与Siah1相互作用，抑制DX2与HSP70相互作用，促进Siah1介导的DX2降解。此外，SDL01结合位点与其他抑制剂不同，因此被认为可能是变构调节剂。 2. SDL01的抗肿瘤效应细胞实验：首先，作者通过在DX2诱导系统中，发现了SDL01可以显著降低DX2诱导细胞的活力，对对照细胞无影响，且在多种肺癌细胞系中观察到DX2水平与SDL01对细胞活力抑制效果呈负相关；接着作者在3D细胞培养和体内实验中，发现SDL01有效减少了肿瘤细胞球的大小、诱导细胞死亡、降低肿瘤生长，且对体重无显著影响。结合特异性：紧接着，作者合成了生物素化的SDL01（biotin - SDL01），证实其特异性结合DX2，KD值为2.3uM，同时确定了DX2的关键结合残基，作者通过突变这些残基发现其会影响DX2与SDL01结合、降解、泛素化及细胞活力和集落形成。 3. SDL01诱导DX2的构象变化接下来，作者通过MD模拟和对接分析表明，SDL01诱导DX2 NFR和GST区域构象变化，形成弯曲结构，拉近DX2与Siah1 SBD距离，增强其相互作用；此外，通过有限蛋白酶消化、体外pull - down和免疫共沉淀等实验证实了这一变化及对蛋白相互作用的影响。 4. SDL01诱导DX2的泛素化位点最后，作者通过LC - MS分析确定K90是SDL01诱导DX2泛素化的潜在靶点，同时发现Siah1负责此过程，此外，K90A突变体还会影响DX2泛素化、稳定性、细胞增殖和转化。总结：本文作者提出了用“变构调节剂”诱导E3泛素连接酶靶向蛋白质的新方法，以DX2为例验证了概念，SDL01可以通过诱导DX2的构象变化，稳定其与Siah1的相互作用，促进泛素化和降解，具有潜在的抗癌药物开发价值。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

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