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

•We found that novel tamoxifen derivatives inhibit proteasome activity.•We revealed the smallest derivative capable of inhibiting proteasome activity.•Culturing of human cells with these compounds resulted in induction of apoptosis.•Docking studies were attempted to elucidate the binding mode of these derivatives.

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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide