Compound activity prediction with dose-dependent transcriptomic profiles and deep learning

Predicting compound activity in assays is a long-standing challenge in drug discovery. Computational models based on compound-induced gene-expression signatures from a single profiling assay have shown promise towards predicting compound activity in other, seemingly unrelated, assays. Applications of such models include predicting mechanisms-of-action (MoA) for phenotypic hits, identifying off-target activities, and identifying polypharmacologies. Here, we introduce Transcriptomics-to-Activity Transformer (TAT) models that leverage gene-expression profiles observed over compound treatment at multiple concentrations to predict compound activity in other biochemical or cellular assays. We built TAT models based on gene-expression data from a RASL-Seq assay to predict the activity of 2,692 compounds in 262 dose response assays. We obtained useful models for 51% of the assays as determined through a realistic held-out set. Prospectively, we experimentally validated the activity predictions of a TAT model in a malaria inhibition assay. With a 63% hit rate, TAT successfully identified several sub-micromolar malaria inhibitors. Our results thus demonstrate the potential of transcriptomic responses over compound concentration and the TAT modeling framework as a cost-efficient way to identify the bioactivities of promising compounds across many assays.