2. Academic Validation
  3. A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor

A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor

  • Eur J Med Chem. 2014 Jan:71:290-305. doi: 10.1016/j.ejmech.2013.11.009.
Makoto Hasegawa 1,  Yukari Yasuda 2,  Makoto Tanaka 2,  Kenya Nakata 3,  Eri Umeda 3,  Yanwen Wang 3,  Chihiro Watanabe 3,  Shoko Uetake 3,  Tatsuki Kunoh 2,  Masafumi Shionyu 2,  Ryuzo Sasaki 2,  Isamu Shiina 4,  Tamio Mizukami 2
Affiliations

Affiliations

  • 1 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.
  • 2 Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
  • 3 Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
  • 4 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.
PMID: 24321833 DOI: 10.1016/j.ejmech.2013.11.009
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.

Keywords

Docking studies; Proteasome inhibitors; Structure–activity relationship (SAR); Tamoxifen derivatives.

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  • HY-113824
    蛋白酶体抑制剂
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