Drug repurposing screen for the rare disease ataxia-telangiectasia

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

SLAS Discovery Pub Date : 2025-01-01 DOI:10.1016/j.slasd.2024.100200

Namrata Jayanth , Gurvan Mahé , Matthew Campbell , Mike Lipkin , Shushant Jain , Rhea van de Bospoort , Jennifer Thornton , Brad Margus , David F. Fischer

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Abstract

Ataxia Telangiectasia (A-T) is a rare, autosomal recessive genetic disorder characterized by a variety of symptoms, including progressive neurodegeneration, telangiectasia, immunodeficiency, and an increased susceptibility to cancer. It is caused by bi-allelic mutations impacting a gene encoding a serine/threonine kinase ATM (Ataxia Telangiectasia Mutated), which plays a crucial role in DNA repair and maintenance of genomic stability. The disorder primarily affects the nervous system, leading to a range of neurological issues, including cerebellar ataxia. The cause of neurodegeneration due to mutations in ATM is still an area of investigation, and currently there is no known treatment to slow down or stop the progression of the neurological problems.

In this collaboration of the A-T Children's Project (ATCP) with Charles River Discovery, we successfully developed a high-throughput assay using induced pluripotent stem cells (iPSC) from A-T donors to measure DNA damage response (DDR). By measuring the changes in levels of activated phosphorylated CHK2 (p-CHK2), which is a downstream signaling event of ATM, we were able to identify compounds that restore this response in the DDR pathway in A-T derived patient cells. Over 6,000 compounds from small molecule drug repurposing libraries were subsequently screened in the assay developed, leading to identification of several promising in vitro hits.

Using the assay developed and the identified hits opens avenues to investigate potential therapeutics for A-T.

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罕见疾病共济失调-毛细血管扩张的药物再利用筛选。

共济失调毛细血管扩张症（a - t）是一种罕见的常染色体隐性遗传病，其特征是多种症状，包括进行性神经变性、毛细血管扩张、免疫缺陷和对癌症的易感性增加。它是由双等位基因突变影响编码丝氨酸/苏氨酸激酶ATM（共济失调毛细血管扩张突变）的基因引起的，该基因在DNA修复和基因组稳定性的维持中起着至关重要的作用。这种疾病主要影响神经系统，导致一系列神经问题，包括小脑性共济失调。由ATM突变引起的神经退行性变的原因仍是一个研究领域，目前还没有已知的治疗方法来减缓或阻止神经问题的进展。在a -t儿童项目（ATCP）与Charles River Discovery的合作中，我们成功开发了一种使用来自a -t供体的诱导多能干细胞（iPSC）来测量DNA损伤反应（DDR）的高通量测定方法。通过测量活化磷酸化CHK2 （p-CHK2）水平的变化，这是ATM的下游信号事件，我们能够识别在a - t衍生的患者细胞中恢复DDR途径中这种反应的化合物。随后，从小分子药物再利用文库中筛选了6000多种化合物，并确定了几种有前景的体外命中。使用开发的检测方法和确定的命中点为研究A-T的潜在治疗方法开辟了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

SLAS Discovery Chemistry-Analytical Chemistry

CiteScore

7.00

自引率

3.20%

发文量

审稿时长

39 days

期刊介绍： Advancing Life Sciences R&D: SLAS Discovery reports how scientists develop and utilize novel technologies and/or approaches to provide and characterize chemical and biological tools to understand and treat human disease. SLAS Discovery is a peer-reviewed journal that publishes scientific reports that enable and improve target validation, evaluate current drug discovery technologies, provide novel research tools, and incorporate research approaches that enhance depth of knowledge and drug discovery success. SLAS Discovery emphasizes scientific and technical advances in target identification/validation (including chemical probes, RNA silencing, gene editing technologies); biomarker discovery; assay development; virtual, medium- or high-throughput screening (biochemical and biological, biophysical, phenotypic, toxicological, ADME); lead generation/optimization; chemical biology; and informatics (data analysis, image analysis, statistics, bio- and chemo-informatics). Review articles on target biology, new paradigms in drug discovery and advances in drug discovery technologies. SLAS Discovery is of particular interest to those involved in analytical chemistry, applied microbiology, automation, biochemistry, bioengineering, biomedical optics, biotechnology, bioinformatics, cell biology, DNA science and technology, genetics, information technology, medicinal chemistry, molecular biology, natural products chemistry, organic chemistry, pharmacology, spectroscopy, and toxicology. SLAS Discovery is a member of the Committee on Publication Ethics (COPE) and was published previously (1996-2016) as the Journal of Biomolecular Screening (JBS).