USP41 Inhibitors

Chemical inhibitors of USP41 employ a variety of mechanisms to impact its function within cellular processes. Trichostatin A, a known histone deacetylase inhibitor, increases the acetylation of histones, which can lead to alterations in chromatin structure. These alterations have downstream effects on DNA accessibility, which can inhibit the activity of USP41 by changing its interaction with chromatin or its substrate proteins. Chloroquine, by increasing the pH of lysosomes, interferes with degradation pathways such as autophagy. The disruption to these pathways can affect the turnover or recycling of USP41, ultimately leading to its functional inhibition. MG132 and Bortezomib are proteasome inhibitors that cause an accumulation of polyubiquitinated proteins. This saturation of the ubiquitin-proteasome system can hinder USP41's ability to bind and process its substrates, which is essential for its deubiquitination activity.

Other compounds, such as Eeyarestatin I, interfere with the endoplasmic reticulum-associated degradation pathway by inhibiting the p97 ATPase, leading to an accumulation of misfolded proteins in the ER which can affect the function of USP41. Lactacystin and Epoxomicin, both proteasome inhibitors, lead to the accumulation of ubiquitinated proteins. This accumulation can compete with or saturate USP41, reducing its effectiveness. Fulvestrant, by targeting estrogen receptors for proteasomal degradation, can indirectly inhibit USP41 by occupying the proteasome and limiting USP41's access to its substrates. Withaferin A binds to and inhibits proteasomal activity, which can cause an accumulation of proteins that normally require USP41 for deubiquitination. O-Phenanthroline, a metal ion chelator, although not directly inhibiting USP41, can affect various metal-dependent enzymes and cellular pathways that indirectly influence the activity of USP41. Finally, MLN4924 and Ginkgolic Acid act upstream by inhibiting NEDD8-activating enzyme and SUMO-activating enzyme respectively, affecting the turnover of ubiquitin chains and SUMOylation processes that can impact the functional role of USP41.