Gerckens Michael, Schorpp Kenji, Pelizza Francesco, Wögrath Melanie, Reichau Kora, Ma Huilong, Dworsky Armando-Marco, Sengupta Arunima, Stoleriu Mircea Gabriel, Heinzelmann Katharina, Merl-Pham Juliane, Irmler Martin, Alsafadi Hani N, Trenkenschuh Eduard, Sarnova Lenka, Jirouskova Marketa, Frieß Wolfgang, Hauck Stefanie M, Beckers Johannes, Kneidinger Nikolaus, Behr Jürgen, Hilgendorff Anne, Hadian Kamyar, Lindner Michael, Königshoff Melanie, Eickelberg Oliver, Gregor Martin, Plettenburg Oliver, Yildirim Ali Önder, Burgstaller Gerald
Institute of Lung Biology and Disease (ILBD) and Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Sci Adv. 2021 Dec 24;7(52):eabb3673. doi: 10.1126/sciadv.abb3673. Epub 2021 Dec 22.
Fibrogenic processes instigate fatal chronic diseases leading to organ failure and death. Underlying biological processes involve induced massive deposition of extracellular matrix (ECM) by aberrant fibroblasts. We subjected diseased primary human lung fibroblasts to an advanced three-dimensional phenotypic high-content assay and screened a repurposing drug library of small molecules for inhibiting ECM deposition. Fibrotic Pattern Detection by Artificial Intelligence identified tranilast as an effective inhibitor. Structure-activity relationship studies confirmed -(2-butoxyphenyl)-3-(phenyl)acrylamides (N23Ps) as a novel and highly potent compound class. N23Ps suppressed myofibroblast transdifferentiation, ECM deposition, cellular contractility, and altered cell shapes, thus advocating a unique mode of action. Mechanistically, transcriptomics identified SMURF2 as a potential therapeutic target network. Antifibrotic activity of N23Ps was verified by proteomics in a human ex vivo tissue fibrosis disease model, suppressing profibrotic markers SERPINE1 and CXCL8. Conclusively, N23Ps are a novel class of highly potent compounds inhibiting organ fibrosis in patients.
纤维化过程会引发致命的慢性疾病，导致器官衰竭和死亡。潜在的生物学过程包括异常成纤维细胞诱导细胞外基质（ECM）大量沉积。我们将患病的原代人肺成纤维细胞进行了先进的三维表型高内涵分析，并筛选了一个用于抑制ECM沉积的小分子药物重新利用文库。通过人工智能进行的纤维化模式检测确定曲尼司特是一种有效的抑制剂。构效关系研究证实-(2-丁氧基苯基)-3-(苯基)丙烯酰胺（N23P）是一类新型的高效化合物。N23P抑制肌成纤维细胞转分化、ECM沉积、细胞收缩性并改变细胞形状，从而表明其独特的作用方式。从机制上讲，转录组学确定SMURF2是一个潜在的治疗靶点网络。在人离体组织纤维化疾病模型中，蛋白质组学验证了N23P的抗纤维化活性，抑制了促纤维化标志物SERPINE1和CXCL8。总之，N23P是一类新型的高效化合物，可抑制患者的器官纤维化。
