Structure-Based Design of Inhibitors Selective for Human Proteasome beta 2c or beta 2i Subunits
Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the beta 1c, beta 1i, beta 5c, and beta 5i subunits exploit the differences in the substrate-binding channels identified by X-...
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Published in | Journal of medicinal chemistry Vol. 62; no. 3; pp. 1626 - 1642 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
Amer Chemical Soc
14.02.2019
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Subjects | |
Online Access | Get full text |
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Summary: | Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the beta 1c, beta 1i, beta 5c, and beta 5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting beta 2c or beta 2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the beta 2c- and beta 2i-selective-compounds LU-002c (4; IC50 beta 2c: 8 nM, IC50 beta 2i/beta 2c: 40-fold) and LU-002i (5; IC50 beta 2i: 220 nM, IC50 beta 2c/beta 2i: 45-fold), respectively. Co-crystal structures with beta 2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of beta 2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors. |
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ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/acs.jmedchem.8b01884 |