Current strategies and progress for targeting the "undruggable" transcription factors

Abstract

Transcription factors (TFs) specifically bind to DNA, recruit cofactor proteins and modulate target gene expression, rendering them essential roles in the regulation of numerous biological processes. Meanwhile, mutated or dysregulated TFs are involved in a variety of human diseases. As multiple signaling pathways ultimately converge at TFs, targeting these TFs directly may prove to be more specific and cause fewer side effects, than targeting the upfront conventional targets in these pathways. All these features together endue TFs with great potential and high selectivity as therapeutic drug targets. However, TFs have been historically considered "undruggable", mainly due to their lack of structural information, especially about the appropriate ligand-binding sites and protein-protein interactions, leading to relatively limited choices in the TF-targeting drug design. In this review, we summarize the recent progress of TF-targeting drugs and highlight certain strategies used for targeting TFs, with a number of representative drugs that have been approved or in the clinical trials as examples. Various approaches in targeting TFs directly or indirectly have been developed. Common direct strategies include aiming at defined binding pockets, proteolysis-targeting chimaera (PROTAC), and mutant protein reactivation. In contrast, the indirect ones comprise inhibition of protein-protein interactions between TF and other proteins, blockade of TF expression, targeting the post-translational modifications, and targeting the TF-DNA interactions. With more comprehensive structural information about TFs revealed by the powerful cryo-electron microscopy technology and predicted by machine-learning algorithms, plus more efficient compound screening platforms and a deeper understanding of TF-disease relationships, the development of TF-targeting drugs will certainly be accelerated in the near future.

Keywords: PROTAC; drug discovery; post-translational modification; protein-protein interaction; transcription factor; undruggable.

Fig. 1. Targeting the androgen receptor (AR) signaling pathway.

Schematic representation showing the regulation of AR downstream genes by small-molecule modulators. a Androgens or SARMs bind to AR LBD and induce conformational changes that facilitate the recruitment of coactivators and activation of gene expression. b The binding of antagonists to LBD blocks the AR signaling pathway. c, d The binding of PROTAC molecules to AR LBD (c) or DBD (d) promotes proteasome-mediated degradation of AR and decreases the activity of AR signaling pathway.

Fig. 2. Targeting the HIF-2α signaling pathway.

Under normoxia, HIF-2α protein is hydroxylated and degraded to maintain a low level. Under hypoxia, HIF-2α accumulates and dimerizes with ARNT to active target gene expression. PHD inhibitors block HIF-2α degradation and activate the HIF-2α signaling pathway. The binding of an antagonist disrupts HIF-2α/ARNT interaction and blocks the HIF-2α signaling pathway. The binding of an agonist enhances HIF-2α/ARNT interaction and activates target gene expression.