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

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.

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