Development of a Kidney Calcification Inhibitor Employing Image-Based Profiling: A Proof-of-Concept Study,ACS Pharmacology & Translational Science

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Development of a Kidney Calcification Inhibitor Employing Image-Based Profiling: A Proof-of-Concept Study
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-11-23 , DOI: 10.1021/acsptsci.0c00153
Anna Kletzmayr ₁ , Melina Bigler ₁ , Elita Montanari ₁ , Makoto Kuro-O ₂ , Hirosaka Hayashi ₂ , Mattias E Ivarsson ₃ , Jean-Christophe Leroux ₁

Affiliation

Kidney calcification increases the risk of chronic kidney disease. However, to date, renal calcium phosphate crystallization, a main initiating and driving factor of kidney calcification, has not been explored as a drug target. Pre-clinical drug development is hampered by limited knowledge on the broad range of kidney calcification disorders, characterized by a multifactorial process of disease progression. In this work, we first established an in vitro calcification profiling platform to accelerate pre-clinical drug discovery. The image-based profiling assay allowed the rapid testing of several ionic stimuli and/or inhibitory molecules. We then leveraged a previously established library of inositol hexakisphosphate analogues to identify a renal calcium phosphate inhibitor. A lead compound showed in vitro and in vivo efficacy to prevent calcium phosphate-induced kidney damage. In conclusion, this work reports a renal calcium phosphate inhibitor that could efficiently reduce kidney damage and emphasizes the utility and translational value of the in vitro calcification platform.

中文翻译：

使用基于图像的分析开发肾钙化抑制剂：概念验证研究

肾脏钙化会增加慢性肾脏病的风险。然而，迄今为止，肾钙化的主要启动和驱动因素肾磷酸钙结晶尚未作为药物靶点进行探索。临床前药物开发受到对范围广泛的肾脏钙化疾病的了解有限，其特点是疾病进展的多因素过程。在这项工作中，我们首先建立了一个体外钙化分析平台，以加速临床前药物的发现。基于图像的分析分析允许快速测试几种离子刺激和/或抑制分子。然后，我们利用先前建立的六磷酸肌醇类似物库来鉴定肾磷酸钙抑制剂。一种先导化合物显示在体外和体内预防磷酸钙引起的肾损伤的功效。总之，这项工作报告了一种可以有效减少肾脏损伤的肾磷酸钙抑制剂，并强调了体外钙化平台的实用性和转化价值。

更新日期：2020-12-12

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