Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state

Omics-based technologies are driving major advances in precision medicine, but efforts are still required to consolidate their use in drug discovery. In this work, we exemplify the use of multi-omics to support the development of 3-chloropiperidines, a new class of candidate anticancer agents. Combined analyses of transcriptome and chromatin accessibility elucidated the mechanisms underlying sensitivity to test agents. Furthermore, we implemented a new versatile strategy for the integration of RNA- and ATAC-seq (Assay for Transposase-Accessible Chromatin) data, able to accelerate and extend the standalone analyses of distinct omic layers. This platform guided the construction of a perturbation-informed basal signature predicting cancer cell lines' sensitivity and to further direct compound development against specific tumor types. Overall, this approach offers a scalable pipeline to support the early phases of drug discovery, understanding of mechanisms, and potentially inform the positioning of therapeutics in the clinic.

Automated summary

This study demonstrates the use of multi-omics to support the development of a new class of candidate anticancer agents. Combined analysis of transcriptome and chromatin accessibility identified mechanisms underlying sensitivity to test agents. A versatile strategy for integrating RNA- and ATAC-seq data was implemented to accelerate and extend standalone analyses. This approach offers a scalable pipeline for early drug discovery and understanding of mechanisms.