USP28 Inhibitors

USP28 inhibitors constitute a class of chemical compounds specifically designed to interact with the enzyme ubiquitin-specific protease 28 (USP28), which plays a critical role in the ubiquitin-proteasome system (UPS). USP28 is one of the many deubiquitinating enzymes (DUBs) that meticulously regulate the process of ubiquitination, a reversible post-translational modification where ubiquitin, a small regulatory protein, is attached to a substrate protein. This attachment serves as a signal for various cellular processes, mostly known for targeting proteins for degradation in the proteasome. However, ubiquitination also plays a part in other cellular processes such as cell cycle regulation, DNA repair, and signal transduction. USP28 inhibitors are designed to bind to the active site of USP28 or to its specific substrate-binding regions, blocking its deubiquitinating activity. By doing so, these inhibitors can modulate the stability of proteins that are substrates of USP28, which can have various downstream effects on cellular functions.

The development of USP28 inhibitors involves a complex interplay of chemistry and biology. The chemical structures of these inhibitors are often complex and require precise molecular design to ensure specificity and efficacy in binding to USP28. The design process typically involves the identification of key residues in the enzyme's active site and the development of molecules that can interact with these residues either through hydrogen bonding, hydrophobic interactions, or other types of chemical bonds. The specificity of USP28 inhibitors is crucial, given that the UPS involves a highly intricate network of enzymes and substrates, and off-target effects could lead to unintended consequences. The potency of these inhibitors is typically measured by their ability to reduce the deubiquitinating activity of USP28 in various in vitro assays, which can include biochemical assays using purified protein or cellular assays where the consequences of USP28 inhibition can be observed in a more complex biological environment.