Senior Scientist Takeda, California, United States
Intestinal fibrosis is a common complication of several enteropathies with inflammatory bowel disease being the major cause. The progression of intestinal fibrosis may lead to intestinal stenosis and obstruction. Even with an increased understanding of tissue fibrogenesis, there is no approved treatment for intestinal fibrosis. To further understand the fibrotic mechanism and address this unmet medical need, we carried out a high throughput small molecule screen covering nearly 5000 compounds with known targets or mechanisms, which have passed Phase I clinical trial or have been approved by the FDA. The screen was performed using human intestinal myofibroblasts under pro-fibrotic TNFα stimulus. As CXCL10 is one of the most up-regulated biomarkers in intestinal inflammatory-associated fibroblasts, we used CXCL10 as a secretory biomarker as a readout for TNFα signaling modulation. In parallel, we used cell painting, a scalable image-based morphology assay, to identify compounds that are able to morphologically reverse the activated fibrotic phenotype back to normal. By using two divergent analytical methods, we identified compounds and target classes that are shared between the two approaches and a few major targets that are unique to each individual method. We validated the primary screen hits with other pro-fibrotic stimuli treated human intestinal myofibroblast cell types. The target ID platform described here represents significant improvements over conventional methods by incorporating a multi-parametric phenotypic approach using disease-relevant cells and stimuli.
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