Targeting Intrinsically Disordered Transcription Factors: Changing the Paradigm

Increased understanding of intrinsically disordered proteins (IDPs) and protein regions has revolutionized our view of the relationship between protein structure and function. Data now support that IDPs can be functional in the absence of a single, fixed, three-dimensional structure. Due to their dynamic morphology, IDPs have the ability to display a range of kinetics and affinity depending on what the system requires, as well as the potential for large-scale association. Although several studies have shed light on the functional properties of IDPs, the class of intrinsically disordered transcription factors (TFs) is still poorly characterized biophysically due to their combination of ordered and disordered sequences. In addition, TF modulation by small molecules has long been considered a difficult or even impossible task, limiting functional probe development. However, with evolving technology, it is becoming possible to characterize TF structure-function relationships in unprecedented detail and explore avenues not available or not considered in the past. Here we provide an introduction to the biophysical properties of intrinsically disordered TFs and we discuss recent computational and experimental efforts toward understanding the role of intrinsically disordered TFs in biology and disease. We describe a series of successful TF targeting strategies that have overcome the perception of the "undruggability" of TFs, providing new leads on drug development methodologies. Lastly, we discuss future challenges and opportunities to enhance our understanding of the structure-function relationship of intrinsically disordered TFs.