title: Functional Identification of Target by Expression Proteomics (FITExP) reveals protein targets and highlights mechanisms of action of small molecule drugs.
abstract: Phenomenological screening of small molecule libraries for anticancer activity yields potentially interesting candidate molecules, with a bottleneck in the determination of drug targets and the mechanism of anticancer action. We have found that, for the protein target of a small-molecule drug, the abundance change in late apoptosis is exceptional compared to the expectations based on the abundances of co-regulated proteins. Based on this finding, a novel method to drug target deconvolution is proposed. In a proof of principle experiment, the method yielded known targets of several common anticancer agents among a few (often, just one) likely candidates identified in an unbiased way from cellular proteome comprising more than 4,000 proteins. A validation experiment with a different set of cells and drugs confirmed the findings. As an additional benefit, mapping most specifically regulated proteins on known protein networks highlighted the mechanism of drug action. The new method, if proven to be general, can significantly shorten drug target identification, and thus facilitate the emergence of novel anticancer treatments.
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheelesväg 2, SE-17 177 Stockholm, Sweden.
authors.forename: Alexey
authors.initials: A
authors.lastname: Chernobrovkin
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheelesväg 2, SE-17 177 Stockholm, Sweden.|Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Marin-Vicente
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Neus
authors.initials: N
authors.lastname: Visa
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheelesväg 2, SE-17 177 Stockholm, Sweden.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zubarev
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D004317:Doxorubicin / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D020543:Proteome / Q000187:drug effects*; D040901:Proteomics; D011799:Quinazolines / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D020543:Proteome; D011799:Quinazolines; D054852:Small Molecule Libraries; D013876:Thiophenes; D004317:Doxorubicin; C068874:raltitrexed; D017239:Paclitaxel; D005472:Fluorouracil; D002166:Camptothecin; D008727:Methotrexate