Proteasome inhibitors as anticancer agents.

INTRODUCTION: The therapeutic targeting of the ubiquitin-proteasome pathway (UPP) through inhibitors of the 20S proteasome core proteolytic activities has revolutionized the treatment of hematological malignancies and is paving the way for its extension to solid tumors. AREAS COVERED: This review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib. The development of selective and potent proteasome inhibitors with improved pharmacological properties is described from the synthesis to their basic biological, and clinical validation. EXPERT OPINION: Proteasome inhibitors have transformed the treatment landscape for hematological malignancies and hold great promise for cancer therapy. Combination therapies targeting multiple pathways, the development of novel inhibitors or 'hybrid-inhibitors,' and the optimization of treatment protocols are key areas for future exploration. The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood-brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic 'working on' aspect for the near future.