Development of proteasome inhibitors in oncology and autoimmune diseases.
The proteasome is a multicatalytic protease complex that mediates the controlled degradation of intracellular proteins, including key components of pathways that contribute to cancer cell growth and immune cell signaling. Validation for the proteasome as a therapeutic target in oncology was provided by bortezomib, a proteasome inhibitor that was approved for the treatment of multiple myeloma in 2003. Since that time, a number of structurally and mechanistically distinct proteasome inhibitors have entered clinical development in oncology. In this review, the chemical properties, preclinical antitumor activities and early clinical trials of these next-generation proteasome inhibitors are described and the potential for future proteasome inhibitor development in autoimmune indications is discussed.
Bennett
Mark K
MK
Proteolix Inc., 333 Allerton Avenue, South San Francisco, CA 94080, USA. mkbennett@proteolix.com
Kirk
Christopher J
CJ
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy; D015853:Cysteine Proteinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007155:Immunologic Factors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex