Non-covalent immunoproteasome inhibitors: virtual screening and in vitro test on β1i /β5i subunits

Abstract

Immunoproteasome inhibition is a challenging strategy for the treatment of hematological malignancies, autoimmune and inflammatory diseases [1,2]. The search for non-covalent inhibitors of the immunoproteasome β1i/β5i catalytic subunits could be a new strategy to avoid the drawbacks of the known covalent inhibitors. Here, we report the biological evaluation of thirty-four compounds selected from commercial libraries. A virtual screening strategy including a dynamic pharmacophore modeling approach onto the β1i subunit and a pharmacophore/docking approach onto the β5i subunit aided the identification of these hits [3]. Compound 3 is the most active onto β1i subunit with Ki = 11.84±1.63 µM, compound 17 showed Ki = 12.50±0.77 µM onto β5i subunit. Compound 2 showed inhibitory activity on both subunits (Ki = 12.53±0.18 Ki = 31.95±0.81 onto β1i subunit and β5i subunit, respectively). The hit compounds identified represent an interesting starting point for further optimization.