%0 Journal Article
%A Carraro, Caterina
%A Bonaguro, Lorenzo
%A Schulte-Schrepping, Jonas
%A Horne, Arik
%A Oestreich, Marie
%A Warnat-Herresthal, Stefanie
%A Helbing, Tim
%A De Franco, Michele
%A Händler, Kristian
%A Mukherjee, Sach
%A Ulas, Thomas
%A Gandin, Valentina
%A Goettlich, Richard
%A Aschenbrenner, Anna Christin
%A Schultze, Joachim L
%A Gatto, Barbara
%T Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state.
%J eLife
%V 11
%@ 2050-084X
%C Cambridge
%I eLife Sciences Publications
%M DZNE-2022-01569
%P e78012
%D 2022
%Z CC BY: https://creativecommons.org/licenses/by/4.0/
%X 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.
%K Chromatin
%K Precision Medicine
%K RNA
%K Transcriptome
%K Transposases: metabolism
%K chromatin accessibility (Other)
%K computational biology (Other)
%K drug candidate (Other)
%K human (Other)
%K mechanism of action (Other)
%K multi-omics (Other)
%K sensitivity ML prediction (Other)
%K systems biology (Other)
%K transcriptome (Other)
%K Chromatin (NLM Chemicals)
%K RNA (NLM Chemicals)
%K Transposases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36043458
%2 pmc:PMC9433094
%R 10.7554/eLife.78012
%U https://pub.dzne.de/record/165276