title: HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.
abstract: Hepatocyte nuclear factor (HNF)4α is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic β cells. Although fatty acids were found to occupy the HNF4α ligand-binding pocket and were proposed to act as ligands, there is controversy about both the nature of HNF4α ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4α antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4α with high affinity and modulated the expression of known HNF4α target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in vitro and in vivo, although in vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4α raises the possibility that diseases involving HNF4α, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4α activity.
authors: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Alice
authors: A
authors: Kiselyuk
authors: Seung-Hee
authors: SH
authors: Lee
authors: Suzette
authors: S
authors: Farber-Katz
authors: Mingjun
authors: M
authors: Zhang
authors: Sonalee
authors: S
authors: Athavankar
authors: Tom
authors: T
authors: Cohen
authors: Anthony B
authors: AB
authors: Pinkerton
authors: Mao
authors: M
authors: Ye
authors: Paul
authors: P
authors: Bushway
authors: Adam D
authors: AD
authors: Richardson
authors: Heather A
authors: HA
authors: Hostetler
authors: Mariam
authors: M
authors: Rodriguez-Lee
authors: Li
authors: L
authors: Huang
authors: Benjamin
authors: B
authors: Spangler
authors: Layton
authors: L
authors: Smith
authors: Jennifer
authors: J
authors: Higginbotham
authors: John
authors: J
authors: Cashman
authors: Hudson
authors: H
authors: Freeze
authors: Pamela
authors: P
authors: Itkin-Ansari
authors: Marcia I
authors: MI
authors: Dawson
authors: Friedhelm
authors: F
authors: Schroeder
authors: Yong
authors: Y
authors: Cang
authors: Mark
authors: M
authors: Mercola
authors: Fred
authors: F
authors: Levine
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007328:Insulin / Q000235:genetics*; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C586828:1-(2'-chloro-5'-nitrobenzenesulfonyl)-2-methylbenzimidazole; C586829:2-methyl-1-(2-methyl-5-nitrophenylsulfonyl)-1H-benzo(d)imidazole; C496142:3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3 H-benzimidazole-5-carboxamide; D001562:Benzimidazoles; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D047495:PPAR gamma; D012333:RNA, Messenger; D013449:Sulfonamides