title: A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor.
abstract: In a survey of nonpeptide noncovalent inhibitors of the human 20S proteasome, we found that a novel tamoxifen derivative, RID-F (compound 6), inhibits all three protease activities of the proteasome at submicromolar levels. Structure-activity relationship studies revealed that a RID-F analog (RID-F-S*4, compound 25) is the smallest derivative compound capable of inhibiting proteasome activity, with a potency similar to that of RID-F. Kinetic analyses of the inhibition mode and competition experiments involving biotin-belactosin A (a proteasome inhibitor) binding indicated that the RID-F derivatives interact with the protease subunits in a different manner. Culturing of human cells with these compounds resulted in accumulation of ubiquitinated proteins and induction of apoptosis. Thus, the RID-F derivatives may be useful lead chemicals for the generation of a new class of proteasome inhibitors.
authors: Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan. Electronic address: m_hasegawa@nagahama-i-bio.ac.jp.
authors: Makoto
authors: M
authors: Hasegawa
authors: Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors: Yukari
authors: Y
authors: Yasuda
authors: Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors: Makoto
authors: M
authors: Tanaka
authors: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
authors: Kenya
authors: K
authors: Nakata
authors: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
authors: Eri
authors: E
authors: Umeda
authors: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
authors: Yanwen
authors: Y
authors: Wang
authors: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
authors: Chihiro
authors: C
authors: Watanabe
authors: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
authors: Shoko
authors: S
authors: Uetake
authors: Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors: Tatsuki
authors: T
authors: Kunoh
authors: Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors: Masafumi
authors: M
authors: Shionyu
authors: Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors: Ryuzo
authors: R
authors: Sasaki
authors: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan. Electronic address: shiina@rs.kagu.tus.ac.jp.
authors: Isamu
authors: I
authors: Shiina
authors: Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors: Tamio
authors: T
authors: Mizukami
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D061988:Proteasome Inhibitors; D013629:Tamoxifen; D046988:Proteasome Endopeptidase Complex
keywords: Docking studies; Proteasome inhibitors; Structure–activity relationship (SAR); Tamoxifen derivatives