Lung Fibrosis - Collagen I translation inhibitors
Fibrosis represents a large group of diseases that remain without effective treatment. It is caused when a wound healing process goes out of control and progresses into continued scarring in the affected organs. The common denominator across fibrotic processes in different organs is over-production of Collagen Type I. By using our platform, we identify Collagen I translation inhibitors, compounds that are active in reducing the production of Collagen I. This is a novel strategy against fibrotic diseases in multiple organs.
- Three distinct compound clusters with favorable structure-activity relationship (SAR) properties in lead optimization.
- We monitor Collagen I translation by using a pair of labeled tRNApro and tRNAgly isoforms.
- A diverse library of 100,000 compounds was screened, generating a set of 20 million images. The resulting big data was analyzed by our cloud-based platform using proprietary image analysis and machine learning algorithms to identify “hits;” compounds that are actively changing the production of Collagen I.
- Hits were shown to be specific to Collagen I translation and did not inhibit general protein translation. They reduce Collagen I translation in human lung fibroblast cell lines and in primary human lung fibroblasts.
1. PSM Screen: Target-specific tRNA pair
2.3 million images generated per screen
Automatic generation of a clean FRET image
2. High content, cloud-based image analysis
Data generated for 54 million cells
90 different features
Total of 5 billion data points
3. Hit Identification: Big data analysis
4. Lead generation
Reduction of collagen-I protein levels in WI-38 cells following treatment with our compounds. Image demonstrates dose response for three distinct chemotypes of compounds all exhibiting an EC50 of under 300nM