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.

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