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

Makoto Hasegawa, Yukari Yasuda, Makoto Tanaka, Kenya Nakata, Eri Umeda, Yanwen Wang, Chihiro Watanabe, Shoko Uetake, Tatsuki Kunoh, Masafumi Shionyu, Ryuzo Sasaki, Isamu Shiina, Tamio Mizukami

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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.

Original languageEnglish
Pages (from-to)290-305
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume71
DOIs
Publication statusPublished - Jan 7 2014

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Keywords

  • Docking studies
  • Proteasome inhibitors
  • Structure-activity relationship (SAR)
  • Tamoxifen derivatives

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Hasegawa, M., Yasuda, Y., Tanaka, M., Nakata, K., Umeda, E., Wang, Y., Watanabe, C., Uetake, S., Kunoh, T., Shionyu, M., Sasaki, R., Shiina, I., & Mizukami, T. (2014). A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor. European Journal of Medicinal Chemistry, 71, 290-305. https://doi.org/10.1016/j.ejmech.2013.11.009