Structure-Based Design of Pan-Selective Peptide Epoxyketones for the Three Human Immunoproteasome Active Sites

The proteasome inhibitors bortezomib, carfilzomib, and
ixazomib
all act by inhibiting multiple active sites of both constitutive proteasomes
and immunoproteasomes. These clinical anticancer drugs are effective,
but also display side effects, and evidence is amassing that their
toxicity arises from constitutive proteasome inhibition. In this work,
we describe the structure-guided discovery of a new class of pan-immunoproteasome-selective
inhibitors. We identified the peptide epoxyketone BocPip-Ser (8), which targets all three human immunoproteasome active
sites potently and with excellent selectivity over constitutive proteasome
active sites (IC50 values for i-subunits ≤ 0.92
μM; IC50 ratio β1c/β1i: 13, β2c/β2i:
14, β5c/β5i: 18; Table 1 and Figure 3). We propose compound 8 (BocPip-Ser), which is of a similar size and general properties
as carfilzomib, as a lead compound for the development of improved
drugs targeting hematological cancers, and possibly also autoimmune
diseases, driven by immunoproteasome but not constitutive proteasome
activities.