title: Identification of alverine and benfluorex as HNF4α activators.
abstract: The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings, activated the nuclear receptor transcription factor HNF4α. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4α. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path toward the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4α activators.
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, 92037, United States.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Sonalee
authors.initials: S
authors.lastname: Athavankar
authors.forename: Tom
authors.initials: T
authors.lastname: Cohen
authors.forename: Ron
authors.initials: R
authors.lastname: Piran
authors.forename: Alice
authors.initials: A
authors.lastname: Kiselyuk
authors.forename: Fred
authors.initials: F
authors.lastname: Levine
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011437:Propylamines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D011437:Propylamines; D005277:Fenfluramine; C001584:benfluorex; C010846:alverine