TY - JOUR
T1 - A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor
AU - Hasegawa, Makoto
AU - Yasuda, Yukari
AU - Tanaka, Makoto
AU - Nakata, Kenya
AU - Umeda, Eri
AU - Wang, Yanwen
AU - Watanabe, Chihiro
AU - Uetake, Shoko
AU - Kunoh, Tatsuki
AU - Shionyu, Masafumi
AU - Sasaki, Ryuzo
AU - Shiina, Isamu
AU - Mizukami, Tamio
N1 - Funding Information:
The authors thank Mie Tsuchida and Miho Hosoi for technical assistance and Dr. Tetuo Yoshida of Kyowa Hakko Kirin Co. for supplying belactosin A. The authors also thank Drs. Takao Yamori and Reiko Shinkura for helpful discussions. This study was supported by a Health Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan to I.S. and a Grant-in-Aid for Scientific Research on Priority Area “Cancer” from the Ministry of Education, Culture, Sports, Science and Technology, Japan to T.M. M.S. received support from the Platform for Drug Discovery, Informatics, and Structural Life Science of the Ministry of Education, Culture, Sports, Science and Technology, Japan.
PY - 2014/1/7
Y1 - 2014/1/7
N2 - 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.
AB - 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.
KW - Docking studies
KW - Proteasome inhibitors
KW - Structure-activity relationship (SAR)
KW - Tamoxifen derivatives
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UR - http://www.scopus.com/inward/citedby.url?scp=84889002270&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2013.11.009
DO - 10.1016/j.ejmech.2013.11.009
M3 - Article
C2 - 24321833
AN - SCOPUS:84889002270
SN - 0223-5234
VL - 71
SP - 290
EP - 305
JO - CHIM.THER.
JF - CHIM.THER.
ER -