Chemical Screens Identify Drugs that Enhance or Mitigate Cellular Responses to Antibody-Toxin Fusion Proteins
Publication Date
August 24, 2016
Journal
PLOS ONE
Authors
Antonella Antignani, Lesley Mathews Griner, Rajarshi Guha, Nathan Simon, et al
Volume
11
Issue
8
Pages
e0161415
DOI
https://dx.plos.org/10.1371/journal.pone.0161415
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0161415
Scopus
84990946512
Mendeley
http://www.mendeley.com/research/chemical-screens-identify-drugs-enhance-mitigate-cellular-responses-antibodytoxin-fusion-proteins
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Mendeley | Further Information

{"title"=>"Chemical screens identify drugs that enhance or mitigate cellular responses to antibody-toxin fusion proteins", "type"=>"journal", "authors"=>[{"first_name"=>"Antonella", "last_name"=>"Antignani", "scopus_author_id"=>"8212073500"}, {"first_name"=>"Lesley Mathews", "last_name"=>"Griner", "scopus_author_id"=>"56313515000"}, {"first_name"=>"Rajarshi", "last_name"=>"Guha", "scopus_author_id"=>"8439277700"}, {"first_name"=>"Nathan", "last_name"=>"Simon", "scopus_author_id"=>"52464622100"}, {"first_name"=>"Matteo", "last_name"=>"Pasetto", "scopus_author_id"=>"57196321942"}, {"first_name"=>"Jonathan", "last_name"=>"Keller", "scopus_author_id"=>"55360129900"}, {"first_name"=>"Manjie", "last_name"=>"Huang", "scopus_author_id"=>"57191489959"}, {"first_name"=>"Evan", "last_name"=>"Angelus", "scopus_author_id"=>"57195218255"}, {"first_name"=>"Ira", "last_name"=>"Pastan", "scopus_author_id"=>"35391014800"}, {"first_name"=>"Marc", "last_name"=>"Ferrer", "scopus_author_id"=>"37025950600"}, {"first_name"=>"David J.", "last_name"=>"FitzGerald", "scopus_author_id"=>"24288821100"}, {"first_name"=>"Craig J.", "last_name"=>"Thomas", "scopus_author_id"=>"9846038800"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84990946512", "doi"=>"10.1371/journal.pone.0161415", "pmid"=>"27556570", "issn"=>"19326203", "scopus"=>"2-s2.0-84990946512", "pui"=>"612635428"}, "id"=>"557a7e82-809e-3ff3-bc27-1cef792b9864", "abstract"=>"The intersection of small molecular weight drugs and antibody-based therapeutics is rarely studied in large scale. Both types of agents are currently part of the cancer armamentarium. However, very little is known about how to combine them in optimal ways. Immunotoxins are antibody-toxin gene fusion proteins engineered to target cancer cells via antibody binding to surface antigens. For fusion proteins derived from Pseudomonas exotoxin (PE), potency relies on the enzymatic domain of the toxin which catalyzes the ADP-ribosylation of EF2 causing inhibition of protein synthesis leading to cell death. Candidate immunotoxins have demonstrated clear value in clinical trials but generally have not been curative as single agents. Therefore we undertook three screens to discover effective combinations that could act synergistically. From the MIPE-3 library of compounds we identified various enhancers of immunotoxin action and at least one major class of inhibitor. Follow-up experiments confirmed the screening data and suggested that immunotoxins when administered with everolimus or nilotinib exhibit favorable combinatory activity and would be candidates for preclinical development. Mechanistic studies revealed that everolimus-immunotoxin combinations acted synergistically on elements of the protein synthetic machinery, including S61 kinase and 4E-BP1 of the mTORC1 pathway. Conversely, PARP inhibitors antagonized immunotoxins and also blocked the toxicity due to native ADP-ribosylating toxins. Thus, our goal of investigating a chemical library was justified based on the identification of several approved compounds that could be developed preclinically as ‘enhancers’ and at least one class of mitigator to be avoided. [ABSTRACT FROM AUTHOR]", "link"=>"http://www.mendeley.com/research/chemical-screens-identify-drugs-enhance-mitigate-cellular-responses-antibodytoxin-fusion-proteins", "reader_count"=>3, "reader_count_by_academic_status"=>{"Researcher"=>1, "Student > Master"=>2}, "reader_count_by_user_role"=>{"Researcher"=>1, "Student > Master"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>1, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>0}

Scopus | Further Information

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