TY  - JOUR
AU  - Carraro, Caterina
AU  - Bonaguro, Lorenzo
AU  - Schulte-Schrepping, Jonas
AU  - Horne, Arik
AU  - Oestreich, Marie
AU  - Warnat-Herresthal, Stefanie
AU  - Helbing, Tim
AU  - De Franco, Michele
AU  - Händler, Kristian
AU  - Mukherjee, Sach
AU  - Ulas, Thomas
AU  - Gandin, Valentina
AU  - Goettlich, Richard
AU  - Aschenbrenner, Anna Christin
AU  - Schultze, Joachim L
AU  - Gatto, Barbara
TI  - Decoding mechanism of action and sensitivity to drug candidates from integrated transcriptome and chromatin state.
JO  - eLife
VL  - 11
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - DZNE-2022-01569
SP  - e78012
PY  - 2022
N1  - CC BY: https://creativecommons.org/licenses/by/4.0/
AB  - 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.
KW  - Chromatin
KW  - Precision Medicine
KW  - RNA
KW  - Transcriptome
KW  - Transposases: metabolism
KW  - chromatin accessibility (Other)
KW  - computational biology (Other)
KW  - drug candidate (Other)
KW  - human (Other)
KW  - mechanism of action (Other)
KW  - multi-omics (Other)
KW  - sensitivity ML prediction (Other)
KW  - systems biology (Other)
KW  - transcriptome (Other)
KW  - Chromatin (NLM Chemicals)
KW  - RNA (NLM Chemicals)
KW  - Transposases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36043458
C2  - pmc:PMC9433094
DO  - DOI:10.7554/eLife.78012
UR  - https://pub.dzne.de/record/165276
ER  -