ZNRF1 Inhibitors

Chemical inhibitors of ZNRF1 function by modulating the activity of enzymes that phosphorylate proteins interacting with this ubiquitin ligase. For instance, GSK-3 inhibitors such as SB-216763, LiCl, BIO, CHIR99021, Indirubin-3'-monoxime, TWS119, AR-A014418, Tideglusib, and AZD1080 can inhibit the phosphorylation of substrates that may have a role in the function of ZNRF1. By preventing the addition of phosphate groups to these substrates, the inhibitors can alter the interaction between ZNRF1 and its substrates. GSK-3 is known for targeting various proteins for phosphorylation, which can then interact with ZNRF1, affecting its ability to tag these proteins with ubiquitin. Without the appropriate phosphorylation signals, the usual targets of ZNRF1 may not be properly recognized, leading to a decrease in ZNRF1-mediated ubiquitination.

On the other hand, HDAC inhibitors like Valproic Acid, Trichostatin A, and Vorinostat engage in a different mechanism of action. They do not directly inhibit the kinase activity but instead alter the acetylation status of proteins. The change in acetylation can influence the protein-protein interactions that are crucial for ZNRF1 function. Proteins that are normally ubiquitinated by ZNRF1 may have altered acetylation patterns, which can affect how ZNRF1 recognizes and processes these substrates. By changing the acetylation landscape of these proteins, HDAC inhibitors can disrupt the normal function of ZNRF1, leading to reduced ubiquitination of its targets. This modulation of protein acetylation serves as an indirect way to regulate the activity of ZNRF1 without directly competing with its substrate binding or ubiquitin ligase activity.