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bioRxiv · 10.1101/2022.02.21.481294

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

Carraro, C.·Bonaguro, L.·Schulte-Schrepping, J.·Horne, A.·Oestreich, M.·Warnat-Herresthal, S.·Helbing, T.·De Franco, M.·Haendler, K.·Mukherjee, S.·Ulas, T.·Gandin, V.·Goettlich, R.·Aschenbrenner, A.·Schultze, J.·Gatto, B.
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Abstract

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 (3-CePs), a new class of candidate anticancer agents. Combined analyses of transcriptome and chromatin accessibility elucidated the mechanisms underlying sensitivity to test agents. Further, we implemented a new versatile strategy for the integration of RNA-seq and ATAC-seq data, able to accelerate and extend the standalone analyses of distinct omic layers. This platform guided the construction of a perturbation-informed basal signature able to predict cancer cell lines sensitivity and to further direct compound development against specific tumor types. Overall, this approach offered a scalable pipeline to support the early phases of drug discovery, understanding of mechanism and potentially inform the positioning of therapeutics in the clinic.

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Carraro, C., Bonaguro, L., Schulte-Schrepping, J., Horne, A., Oestreich, M., Warnat-Herresthal, S., Helbing, T., De Franco, M., Haendler, K., Mukherjee, S., Ulas, T., Gandin, V., Goettlich, R., Aschenbrenner, A., Schultze, J., Gatto, B.. 2022-02-21. Decoding mechanism of action and susceptibility to drug candidates from integrated transcriptome and chromatin state. https://doi.org/10.1101/2022.02.21.481294

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