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 inJournal of medicinal chemistry Vol. 62; no. 3; pp. 1626 - 1642
Main Authors Xin, Bo-Tao, Huber, Eva M., de Bruin, Gerjan, Heinemeyer, Wolfgang, Maurits, Elmer, Espinal, Christofer, Du, Yimeng, Janssens, Marissa, Weyburne, Emily S., Kisselev, Alexei F., Florea, Bogdan I., Driessen, Christoph, van der Marel, Gijsbert A., Groll, Michael, Overkleeft, Herman S.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 14.02.2019
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
YEAST
MECHANISM
CRYSTAL-STRUCTURE
IMMUNOPROTEASOME
SUBSTRATE
KNOWLEDGE
SITES
GENERATION
BORTEZOMIB
20S PROTEASOMES
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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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01884