High-Throughput Screening Platform in Postnatal Heart Cells and Chemical Probe Toolbox to Assess Cardiomyocyte Proliferation,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

High-Throughput Screening Platform in Postnatal Heart Cells and Chemical Probe Toolbox to Assess Cardiomyocyte Proliferation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-24 , DOI: 10.1021/acs.jmedchem.1c01173
Carmen Carrillo García ₁ , Cora Becker ₂ , Michael Forster ₃ , Stefan Lohmann ₁ , Patricia Freitag ₂ , Stefan Laufer _{3,

4,

5} , Sonja Sievers ₆ , Bernd K Fleischmann _{2,

7} , Michael Hesse ₂ , Dennis Schade _{1,

8}

Affiliation

Restoring lost heart muscle is an attractive goal for cardiovascular regenerative medicine. One appealing strategy is the therapeutic stimulation of cardiomyocyte proliferation, which inter alia remains challenging due to available assay technologies capturing the complex biology. Here, a high-throughput-formatted phenotypic assay platform was established using rodent whole heart-derived cells to preserve the cellular environment of cardiomyocytes. Several readouts allowed the quantification of cycling cardiomyocytes, including a transgenic H2B-mCherry system for unequivocal, automated detection of cardiomyocyte nuclei. A chemical genetics approach revealed pronounced species differences and furnished pan-kinase inhibitors 5 and 36 as potent and robust inducers of endoreplication and acytokinetic mitosis. Combined profiling of the commonly used p38 MAPK inhibitors SB203580 (1), SB239063 (2) and a novel set of skepinone-L (6) derivatives pointed to off-target effects beyond p38 that might be critical for effective cardiomyocyte cytokinesis. Kinome-focused screening eventually furnished TG003 (38) as a novel candidate for stimulating cardiomyocyte proliferation.

中文翻译：

产后心脏细胞高通量筛选平台和评估心肌细胞增殖的化学探针工具箱

恢复失去的心肌是心血管再生医学的一个有吸引力的目标。一种有吸引力的策略是治疗性刺激心肌细胞增殖，由于可用的分析技术捕获复杂的生物学特性，这仍然具有挑战性。在这里，使用啮齿动物全心脏来源的细胞建立了高通量格式的表型测定平台，以保护心肌细胞的细胞环境。多种读数可以对循环心肌细胞进行定量，包括用于明确、自动检测心肌细胞核的转基因 H2B-mCherry 系统。化学遗传学方法揭示了明显的物种差异，并提供了泛激酶抑制剂5和36作为内复制和无细胞动力有丝分裂的有效和稳健的诱导剂。对常用 p38 MAPK 抑制剂 SB203580 ( 1 )、SB239063 ( 2 ) 和一组新型 skepinone-L ( 6 ) 衍生物的综合分析表明，p38 之外的脱靶效应可能对有效的心肌细胞胞质分裂至关重要。以激酶组为重点的筛选最终使 TG003 ( 38 ) 成为刺激心肌细胞增殖的新候选者。

更新日期：2022-01-27

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11