title: Synthetic lethality for linking the mycophenolate mofetil mode of action with molecular disease and drug profiles.
abstract: Systematic study of the effect of mycophenolate mofetil (MMF) on the molecular level in the context of other drugs and molecular disease profiles became possible due to the availability of large scale molecular profiles on both disease characterization and drug mode of action. Such analysis is of particular value in elucidating alternative drug use for addressing clinically unmet needs, and the concept of synthetic lethality provides an alternative tool for such repositioning strategies. Resting on consolidation of transcriptomics data and literature mining, a MMF molecular footprint became available including a set of 170 genes specifically affected by the drug. Analysis of this profile on a molecular pathway level reveals a set of 14 pathways as affected. Next to assignment of molecular pathways and associated diseases synergistic drug combinations are proposed by utilizing the synthetic lethal interaction network. Of particular interest is the combination of MMF with adenosine deaminase inhibitors, sulfasalazine, and other selected drugs interfering with calcium-based regulatory pathways and metabolism. Indeed analysis of drugs in clinical trials positively identifies combinations with MMF in the context of synthetic lethality and affected pathways, particularly in diseases such as multiple sclerosis, vasculitis, GVHD and lupus nephritis. Importantly, the synthetic lethal interaction of the drug mode of action is an interesting basis for rational repositioning strategies by suggesting combinations which exhibit a synergistic rather than a mere additive effect, as for example is evident for the combination of tacrolimus and MMF. Inherent is also the assessment of possible adverse effects of drug combinations.
authors.affiliation: Emergentec Biodevelopment GmbH, 1180 Wien, Austria. johannes.soellner@emergentec.com
authors.forename: Johannes
authors.initials: J
authors.lastname: Söllner
authors.forename: Paul
authors.initials: P
authors.lastname: Mayer
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinzel
authors.forename: Raul
authors.initials: R
authors.lastname: Fechete
authors.forename: Christian
authors.initials: C
authors.lastname: Siehs
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
mesh_terms: D058892:Adenosine Deaminase Inhibitors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D058892:Adenosine Deaminase Inhibitors; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D012460:Sulfasalazine; D009173:Mycophenolic Acid; D002118:Calcium; D016559:Tacrolimus