biostudies-literatureWoo JHHoward Hughes Medical InstituteNHLBI NIH HHSNCI NIH HHSNIH HHS441-451https://www.ebi.ac.uk/biostudies/studies/S-EPMC4506491biostudies-literatureUnknown162(2)Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity.CellElucidating Compound Mechanism of Action by Network Perturbation Analysis.PMC4506491R01CA161061U01 CA168426R01 CA097061S10 OD012351U54 CA1218525R01CA097061R35 CA209896U01 CA1641845U54CA121852-085U01CA1684261U01CA164184-023U01HL111566-02R01 CA161061U01 HL111566Karan CShimoni YWoo JHNicoletti PStockwell BRIyer ALopez GCalifano AYang WSRodriguez Martinez MSubramaniam PBansal MRealubit RMattioli MfalseElucidating Compound Mechanism of Action by Network Perturbation Analysis.Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity.2015-01-01T00:00:00Z2015 Jul2024-11-20T03:22:04.645Z2019-03-27T01:55:21ZS-EPMC45064912618619510.1016/j.cell.2015.05.056