<abstract xmlns="http://www.w3.org/1999/xhtml">
<p>The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as cancer, inflammation, and autoimmune diseases. The development of novel chemical scaffolds of non-peptidic nature, capable of inhibiting different catalytically active subunits of both isoforms, is a viable approach against these diseases. Such compounds are also useful as leads for the development of biochemical probes that enable the studies of the roles of both isoforms in various biological contexts. Here, we present a ligand-based computational design of (immuno)proteasome inhibitors, which  resulted in the amino-substituted <italic>N</italic>-arylpiperidine-based compounds that can inhibit different subunits of the (immuno)proteasome in the low micromolar range. The compounds represent a useful starting point for further structure-activity relationship studies that will, hopefully, lead to non-peptidic compounds that could be used in pharmacological and biochemical  studies of both proteasomes.</p>
</abstract>

The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as cancer, inflammation, and autoimmune diseases. The development of novel chemical scaffolds of non-peptidic nature, capable of inhibiting different catalytically active subunits of both isoforms, is a viable approach against these diseases. Such compounds are also useful as leads for the development of biochemical probes that enable the studies of the roles of both isoforms in various biological contexts. Here, we present a ligand-based computational design of (immuno)proteasome inhibitors, which  resulted in the amino-substituted N-arylpiperidine-based compounds that can inhibit different subunits of the (immuno)proteasome in the low micromolar range. The compounds represent a useful starting point for further structure-activity relationship studies that will, hopefully, lead to non-peptidic compounds that could be used in pharmacological and biochemical  studies of both proteasomes.

Design and synthesis of amino-substituted <italic>N</italic>-arylpiperidinyl-based inhibitors of the (immuno)proteasome

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Design and synthesis of amino-substituted -arylpiperidinyl-based inhibitors of the (immuno)proteasome

The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as...

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome

Publié en ligne: 14 sept. 2023

Pages: 441 - 456

Accepté: 02 juil. 2023

DOI: https://doi.org/10.2478/acph-2023-0032

Mots clés
proteasomes, scaffold morphing, optimization, computational design, selectivity, inhibitors

© 2023 Martina Gobec et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome

Publié en ligne: 14 sept. 2023

Pages: 441 - 456

Accepté: 02 juil. 2023

DOI: https://doi.org/10.2478/acph-2023-0032

Mots clésproteasomes, scaffold morphing, optimization, computational design, selectivity, inhibitors

© 2023 Martina Gobec et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Mots clés
proteasomes, scaffold morphing, optimization, computational design, selectivity, inhibitors