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Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets.
Chembiochem. 2020 Jul 03 [Online ahead of print]C

Abstract

Unbiased morphological profiling of bioactivity, for example, in the cell painting assay (CPA), enables the identification of a small molecule's mode of action based on its similarity to the bioactivity of reference compounds, irrespective of the biological target or chemical similarity. This is particularly important for small molecules with nonprotein targets as these are rather difficult to identify with widely employed target-identification methods. We employed morphological profiling using the CPA to identify compounds that are biosimilar to the iron chelator deferoxamine. Structurally different compounds with different annotated cellular targets provoked a shared physiological response, thereby defining a cluster based on their morphological fingerprints. This cluster is based on a shared mode of action and not on a shared target, that is, cell-cycle modulation in the S or G2 phase. Hierarchical clustering of morphological fingerprints revealed subclusters that are based on the mechanism of action and could be used to predict target-related bioactivity.

Authors+Show Affiliations

Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany. Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, Dortmund, 44227, Germany.Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany.Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany.Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany.Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany.Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany.Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany. Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, Dortmund, 44227, Germany.Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32618075

Citation

Schneidewind, Tabea, et al. "Morphological Profiling Identifies a Common Mode of Action for Small Molecules With Different Targets." Chembiochem : a European Journal of Chemical Biology, 2020.
Schneidewind T, Brause A, Pahl A, et al. Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets. Chembiochem. 2020.
Schneidewind, T., Brause, A., Pahl, A., Burhop, A., Mejuch, T., Sievers, S., Waldmann, H., & Ziegler, S. (2020). Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets. Chembiochem : a European Journal of Chemical Biology. https://doi.org/10.1002/cbic.202000381
Schneidewind T, et al. Morphological Profiling Identifies a Common Mode of Action for Small Molecules With Different Targets. Chembiochem. 2020 Jul 3; PubMed PMID: 32618075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets. AU - Schneidewind,Tabea, AU - Brause,Alexandra, AU - Pahl,Axel, AU - Burhop,Annina, AU - Mejuch,Tom, AU - Sievers,Sonja, AU - Waldmann,Herbert, AU - Ziegler,Slava, Y1 - 2020/07/03/ PY - 2020/06/16/received PY - 2020/07/02/revised PY - 2020/7/4/pubmed PY - 2020/7/4/medline PY - 2020/7/4/entrez KW - antiproliferative KW - cell cycle KW - iron chelators KW - mode of action KW - phenotypic profiling JF - Chembiochem : a European journal of chemical biology JO - Chembiochem N2 - Unbiased morphological profiling of bioactivity, for example, in the cell painting assay (CPA), enables the identification of a small molecule's mode of action based on its similarity to the bioactivity of reference compounds, irrespective of the biological target or chemical similarity. This is particularly important for small molecules with nonprotein targets as these are rather difficult to identify with widely employed target-identification methods. We employed morphological profiling using the CPA to identify compounds that are biosimilar to the iron chelator deferoxamine. Structurally different compounds with different annotated cellular targets provoked a shared physiological response, thereby defining a cluster based on their morphological fingerprints. This cluster is based on a shared mode of action and not on a shared target, that is, cell-cycle modulation in the S or G2 phase. Hierarchical clustering of morphological fingerprints revealed subclusters that are based on the mechanism of action and could be used to predict target-related bioactivity. SN - 1439-7633 UR - https://www.unboundmedicine.com/medline/citation/32618075/Morphological_profiling_enables_the_identification_of_common_mode_of_action_for_small_molecules_with_different_targets L2 - https://doi.org/10.1002/cbic.202000381 DB - PRIME DP - Unbound Medicine ER -
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