ABSTRACT
Intrinsically disordered proteins (IDPs) are critical players in the dynamic control of diverse cellular processes, and provide potential new drug targets because their dysregulation is closely related to many diseases. This review focuses on several medicinal studies that have identified low-molecular-weight inhibitors of IDPs. In addition, clinically relevant liquid-liquid phase separations-which critically involve both intermolecular interactions between IDPs and their posttranslational modification-are analyzed to understand the potential of IDPs as new drug targets.
Subject(s)
Carrier Proteins/metabolism , Drug Discovery , Intrinsically Disordered Proteins/metabolism , Signal Transduction , Animals , Biomarkers , Drug Discovery/methods , Humans , Intrinsically Disordered Proteins/antagonists & inhibitors , Intrinsically Disordered Proteins/chemistry , Intrinsically Disordered Proteins/isolation & purification , Liquid-Liquid Extraction/methods , Protein Binding , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
Essential components of the human circadian clock, BMAL1 and CLOCK, which are intrinsically disordered transcription factors, were expressed and subjected to a fluorescent in vitro binding assay using an E-box DNA fragment. Screening of a chemical library identified 5,8-quinoxalinedione (1), which was found to inhibit binding of the heterodimer BMAL1/CLOCK to E-box at low micromolar concentrations.
