title: Clinical and marketed proteasome inhibitors for cancer treatment.
abstract: The ubiquitin-proteasome pathway (UPP), which influences essential cellular functions including cell growth, differentiation, apoptosis, signal transduction, antigen processing and inflammatory responses, has been considered as one of the most important cellular protein degradation approaches. Proteasome functions as a gatekeeper, which controls the execution of protein degradation and plays a critical role in the ubiquitin-proteasome pathway. The unfolding of the close connection between proteasome and cancer provides a potential strategy for cancer treatment by using proteasome inhibitors. Small molecular inhibitors of varied structures and potency against proteasome have been discovered in recent years, with bortezomib and carfilzomib having been successfully approved for clinical application while some other promising candidates are currently under clinical trials. Herein, we review the development history of drugs and candidates that target the 20S proteasome, structure-activity relationships (SARs) of various proteasome inhibitors, and related completed or ongoing clinical trials.
authors.affiliation: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D001896:Boron Compounds / Q000737:chemistry / Q000627:therapeutic use; D001897:Boronic Acids / Q000737:chemistry / Q000627:therapeutic use; D000069286:Bortezomib; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011719:Pyrazines / Q000737:chemistry / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013912:Threonine / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D001896:Boron Compounds; D001897:Boronic Acids; D007783:Lactones; C554738:ONX 0912; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D013912:Threonine; D000069286:Bortezomib; C527966:delanzomib; C475865:marizomib; C548400:ixazomib; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex; D005998:Glycine