title: Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.
abstract: The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kikuchi
authors.forename: Naoya
authors.initials: N
authors.lastname: Shibayama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamada
authors.forename: Taeko
authors.initials: T
authors.lastname: Wada
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nobuyoshi
authors.forename: Tohru
authors.initials: T
authors.lastname: Izumi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Akutsu
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.forename: Kanako
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Mio
authors.initials: M
authors.lastname: Ohki
authors.forename: Sam-Yong
authors.initials: SY
authors.lastname: Park
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D001897:Boronic Acids; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D015151:Immunoblotting; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011719:Pyrazines; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D001897:Boronic Acids; D010879:Piperazines; D061988:Proteasome Inhibitors; D011719:Pyrazines; D013778:Tetrazolium Salts; D013844:Thiazoles; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C022616:thiazolyl blue