E1 activating inhibitors are a class of compounds that target ubiquitin-activating enzymes (E1 enzymes) within the ubiquitin-proteasome system. These inhibitors hinder the initiation of the ubiquitination process, which is vital for protein degradation. By blocking E1 enzymes, they can impact cellular processes, particularly in cancer cells, leading to potential therapeutic applications. Research in this field continues to explore the development of E1 activating inhibitors as a novel approach to cancer treatment and other diseases where protein degradation plays a significant role.