Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma.
Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics.
Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Clinical Hematology, University Hospital Brno, Brno, Czech Republic.
Lenka
L
Kubiczkova
Ludek
L
Pour
Lenka
L
Sedlarikova
Roman
R
Hajek
Sabina
S
Sevcikova
D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*
D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
bortezomib; multiple myeloma; new-generation proteasome inhibitors