The Evolution and Diversification of Proteasome Inhibitors in Cancer and Beyond

The Ubiquitin-Proteasome System (UPS) is a fundamental intracellular machinery essential for protein homeostasis and the regulation of virtually all cellular processes in eukaryotes, including cell cycle control, signal transduction, and apoptosis. Its dysregulation is intrinsically linked to the pathogenesis of numerous human diseases, most notably cancer, where cancer cells exhibit heightened reliance on the UPS for survival and proliferation, as well as neurodegenerative and autoimmune disorders. This dependency has validated the UPS, particularly the proteasome, as a critical therapeutic target. The clinical success of proteasome inhibitors (PIs) like bortezomib, carfilzomib, and ixazomib in hematological malignancies has revolutionized treatment paradigms and spurred extensive research into novel UPS-targeting strategies. This review provides a comprehensive overview of the evolving landscape of proteasome inhibitors and UPS modulators. We begin by detailing the structure and function of the 20S and 26S proteasomes and the broader role of the UPS in cellular health and disease. We then explore the diverse classes of PIs, from established covalent inhibitors (peptide aldehydes, boronates, epoxyketones, β-lactones) to emerging non-covalent agents and novel chemical scaffolds. The multifaceted mechanisms through which these inhibitors exert their anti-cancer effects—including induction of apoptosis, ER stress, NF-κB pathway modulation, cell cycle arrest, and impairment of DNA damage response—are discussed. The review further examines the clinical landscape, encompassing FDA-approved drugs, agents in clinical development, and the ongoing challenges of efficacy in solid tumors, drug resistance, and toxicity profiles. Emphasis is placed on strategies to overcome these hurdles, such as the development of isoform-selective inhibitors targeting the immunoproteasome for autoimmune conditions and specific cancers, and the crucial role of silico computational methods in modern PI discovery and optimization. Finally, we discuss future directions, including the pursuit of novel binding sites, combination therapies, and the continued exploration of innovative therapeutic modalities like PROTACs, highlighting the dynamic evolution and enduring promise of targeting the UPS in cancer and beyond.