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Publication Abstract from PubMed

Broad-spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer beta5c or beta5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two beta-lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo-isoleucin) or an isopropyl (pseudo-valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for beta5i (IC50 =14 nM) than the valine counterpart. Cell culture experiments demonstrate the cell-permeability of the compounds and X-ray crystallography data highlight them as minimal fragments that occupy primed and non-primed pockets of the active sites of the proteasome. Together, these results qualify beta-lactones as a promising lead-structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.

A Minimal beta-Lactone Fragment for Selective beta5c or beta5i Proteasome Inhibitors.,Groll M, Korotkov VS, Huber EM, de Meijere A, Ludwig A Angew Chem Int Ed Engl. 2015 May 14. doi: 10.1002/anie.201502931. PMID:25973989^[1]

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