6htp

Publication Abstract from PubMed

Subunit-selective proteasome inhibitors are valuable tools to assess the biological function and medicinal relevance of individual proteasome active sites in a specific context. While inhibitors for the beta1c, beta1i, beta5c and beta5i subunits exploit structural differences in the substrate binding channels identified by X-ray crystallography, compounds selectively targeting beta2c or beta2i could not be rationally designed so far due to the high degree of structural similarity of these subunits. Here we report the development, chemical synthesis and biological screening of a compound library that led to the identification of the beta2c- and beta2i-selective compounds LU-002c (4; IC50 beta2c: 8 nM, IC50 beta2i/beta2c: 20-fold) and LU-002i (5; IC50 beta2i: 220 nM, IC50 beta2c/beta2i: 45-fold), respectively. Co-crystal structures with beta2-humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, an elaborate combination of organic syntheses, activity-based protein profiling, yeast mutagenesis and structural biology allowed us to decipher subtle but significant differences of beta2 substrate binding channels and to complete the set of subunit-selective proteasome inhibitors by identifying beta2c- and beta2i-selective compounds.

Structure-based design of inhibitors selective for human proteasome beta2c or beta2i subunits.,Xin BT, Huber E, de Bruin G, Heinemeyer W, Maurits E, Espinal C, Du Y, Janssens M, Weyburne ES, Kisselev A, Florea BI, Driessen C, van der Marel GA, Groll M, Overkleeft HS J Med Chem. 2019 Jan 18. doi: 10.1021/acs.jmedchem.8b01884. PMID:30657666^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.