Bollong Michael J, Yang Baiyuan, Vergani Naja, Beyer Brittney A, Chin Emily N, Zambaldo Claudio, Wang Danling, Chatterjee Arnab K, Lairson Luke L, Schultz Peter G
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
California Institute for Biomedical Research, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2017 May 2;114(18):4679-4684. doi: 10.1073/pnas.1702750114. Epub 2017 Apr 17.
Fibrosis, a disease in which excessive amounts of connective tissue accumulate in response to physical damage and/or inflammatory insult, affects nearly every tissue in the body and can progress to a state of organ malfunction and death. A hallmark of fibrotic disease is the excessive accumulation of extracellular matrix-secreting activated myofibroblasts (MFBs) in place of functional parenchymal cells. As such, the identification of agents that selectively inhibit the transdifferentiation process leading to the formation of MFBs represents an attractive approach for the treatment of diverse fibrosis-related diseases. Herein we report the development of a high throughput image-based screen using primary hepatic stellate cells that identified the antifungal drug itraconazole (ITA) as an inhibitor of MFB cell fate in resident fibroblasts derived from multiple murine and human tissues (i.e., lung, liver, heart, and skin). Chemical optimization of ITA led to a molecule (CBR-096-4) devoid of antifungal and human cytochrome P450 inhibitory activity with excellent pharmacokinetics, safety, and efficacy in rodent models of lung, liver, and skin fibrosis. These findings may serve to provide a strategy for the safe and effective treatment of a broad range of fibrosis-related diseases.
纤维化是一种因物理损伤和/或炎症刺激而导致大量结缔组织积聚的疾病，它几乎影响身体的每个组织，并可能发展到器官功能障碍和死亡的状态。纤维化疾病的一个标志是分泌细胞外基质的活化肌成纤维细胞（MFBs）过度积聚，取代了功能性实质细胞。因此，鉴定能够选择性抑制导致MFBs形成的转分化过程的药物，是治疗多种纤维化相关疾病的一种有吸引力的方法。在此，我们报告了一种基于图像的高通量筛选方法的开发，该方法使用原代肝星状细胞，鉴定出抗真菌药物伊曲康唑（ITA）是源自多种小鼠和人类组织（即肺、肝、心和皮肤）的驻留成纤维细胞中MFB细胞命运的抑制剂。对ITA进行化学优化，得到了一种分子（CBR-096-4），该分子没有抗真菌和抑制人细胞色素P450的活性，在肺、肝和皮肤纤维化的啮齿动物模型中具有优异的药代动力学、安全性和疗效。这些发现可能为安全有效地治疗多种纤维化相关疾病提供一种策略。
