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. © 2014 the authors. journal of cellular and molecular medicine published by john wiley & sons ltd and foundation for cellular and molecular medicine.