Fig. 6

Current therapeutic strategies to target transcriptional co-activators. a Targeting the co-activators (CoA) with small molecule inhibitors (SMIs) is a widely used strategy to inhibit the function of the CoAs. The SMI interacts with binding residues on the target protein surface and mediates either orthosteric or allosteric inhibition. During orthosteric inhibition, SMIs directly block protein-protein interactions with their binding partners. Allosteric inhibition is achieved when the SMIs bind to the target proteins and induce conformational changes on the binding surface, thereby dampening its activity. SMIs have also been reported to bind to functional domain (FD), like the bromodomains, of the transcriptional CoAs, consequently preventing the interaction between the acetyl groups and the bromodomains to inhibit transcriptional activation. b Molecular glue degraders are another potential therapeutic strategy. The interaction between an E3 ubiquitin ligase and the transcriptional co-activators are induced by the molecular glue, which promotes ubiquitination-mediated degradation of the co-activators. c The most rapidly growing heterobifunctional protein degrading system is proteolysis-targeting chimeras (PROTACs). The degradation system of PROTACs comprises an anchor and a warhead, which is connected by a linker molecule. The warhead binds to the protein of interest (POI), while the anchor recruits E3 ubiquitin ligase, thereby hijacking the ubiquitin proteasome system of the cell to degrade the POI. This figure was created using BioRender (https://biorender.com/)