A study from Henry W. B. Johnson discovered and described KZR-504 as a highly selective inhibitor of immunoproteasome low molecular mass polypeptide 2 (LMP2). Immunoproteasome is always expressed in nonhematopoietic cells exposed to inflammatory cytokines. Immunoproteasome also plays an important role in antigen presentation, influencing cytokine production, and T-cell differentiation and survival.

Since the two peptide inhibitors Bortezomib and Carfilzomib approved by FDA, inhibiting proteasome has proven an effective therapeutic strategy to target the plasma cell neoplasm, multiple myeloma.

Firstly in the study, the authors screened a focused library of epoxy ketones, which revealed a series of potent dipeptides. Then the authors found a highly selective inhibitor KZR-504. And KZR-504 exhibits IC50 values of 51 nM, 4.274 μM for LMP2 and LMP7, respectively.

Based on the attractive potency and selectivity profile of KZR-504, the authors also evaluated it in vivo. As a result, KZR-504 exhibits significantly lower permeability that other compounds tested in the study. Evaluating the inhibition of LMP2, and anti-targets LMP7 and β5, in mouse tissues reveals that KZR-504 is both selective and potent in vivo with >50% target inhibition achieved at >1 mg/kg in all tissues tested except brain. However, KZR-504 appeared to have little to no effect on cytokine production.

Furthermore, KZR-504 has a selective dose of administration  in vivo. Collectively, the desirable properties of KZR-504 make it an excellent addition to the armory of molecules available in the hunt for a more complete understanding of proteasome biology.

Johnson HWB, et al. Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit. ACS Med Chem Lett. 2017 Mar 9;8(4):413-417.