Deep-learning-based de novo discovery and design of therapeutics that reverse disease-associated transcriptional phenotypes

Clinical Snapshot

Key Findings

• P Value: Not specified in abstract

• Effect Size: Two unique compound series for hepatocellular carcinoma with favorable selectivity

• Primary Outcome: Successful identification of compounds that reverse disease-associated transcriptomic signatures

• Nnt Or Sensitivity: Platform identified novel anti-fibrotic compounds and repurposing candidates

• Confidence Interval: Not specified in abstract

Clinical Application

Requires significant computational resources and specialized expertise; compounds need clinical development Relevant to Australian cancer and respiratory medicine practice; TGA approval would be required for any resulting therapeutics; potential for collaboration with Australian bioinformatics centers Patients with hepatocellular carcinoma and idiopathic pulmonary fibrosis, potentially expandable to other diseases

Abstract

Identifying drugs that reverse disease-associated transcriptomic features has been widely explored for drug repurposing, but its potential for de novo drug discovery remains underexplored. Here, we present gene expression profile predictor on chemical structures (GPS), a deep-learning-based drug discovery platform, guided by transcriptomic features, that screens large compound libraries and optimizes lead molecules. We first develop a model that captures transcriptomic perturbation signatures solely from chemical structures and deploy it to library compounds. We refine scoring methods and employ a tree-search method for optimization. By incorporating structure-gene-activity relationships, we uncover drug mechanisms from transcriptomic data. We evaluate GPS across multiple diseases and conduct extensive validation in two cases. In hepatocellular carcinoma, we discover two unique compound series with favorable cellular selectivity and in vivo efficacy. In idiopathic pulmonary fibrosis, we identify one repurposing candidate and one novel anti-fibrotic compound by reversing gene expression of multiple distinct cell types derived from single-cell transcriptomics.

References

1. 1.Xing, J., Tan, M., Leshchiner, D., Sun, M., Abdelgied, M., Huang, L., Paithankar, S., Uhl, K., Shankar, R., Lisabeth, E., Aleiwi, B., Jager, T., Lawson, C., Chen, R., Giletto, M., Girgis, R., Neubig, R. R., So, S., Ellsworth, E., Li, X., Chua, M.-S., Zhou, J., & Chen, B. (2026). Deep-learning-based de novo discovery and design of therapeutics that reverse disease-associated transcriptional phenotypes. Cell. https://doi.org/10.1038/s41467-020-15647-5