Abstract
Inhibition of the immunoproteasome (iCP) offers new opportunities in the treatment of cancer, autoimmune disorders and neurodegenerative diseases. Inspired by the success of boronic acids as proteasome inhibitors we have complied a virtual library of commercially available 5- and 6-membered borocycles and performed a structure based virtual screening against the chymotrypsin-like (β5i) subunit of the iCP. The top scored docking poses were visually inspected to select compounds for experimental testing. Six compounds with 5-membered ring and another six compounds with 6-membered ring were subjected to biochemical tests. All compounds exhibited detectable inhibitory activity at 100 µM concentration and these are the first reported cyclic boronic acid inhibitors of the iCP. Structural variations including the ring size and the substitution of the borocyles and the substitution pattern of the attached aromatic ring resulted in no major variation of the inhibitory activity. We propose that the evaluation of larger cycling boronic acid libraries is needed to fully elucidate the potential of these structures.
Highlights
The proteasome is a multiprotein complex which has multicatalytic properties
The proteasome can be divided into two parts: the 19S regulatory particle (19S RP) and the 20S catalytic core particle (20S CP)
Inspired by the success of boronic acids as immunoproteasome inhibitors we have initiated a hit finding campaign with the objective of discovering cyclic boronic acids as inhibitors of the β5i subunit of iCP. This type of compounds is well known by medicinal chemists, and three cyclic boronic acid drugs have been approved by the Food and Drug Administration iCP (FDA) recently (Table 1)
Summary
The proteasome is a multiprotein complex which has multicatalytic properties. It assists in the degradation of damaged proteins into short peptide sequences and represents the crucial part of the ubiquitin-proteasome system [1,2,3,4]. Several inhibitors of the iCP were reported to date; of the majority have peptidic structures, which result in poor pharmacokinetic properties in most of the cases. Another notable issue is the limited selectivity against the CP [1, 6]. Inspired by the success of boronic acids as immunoproteasome inhibitors we have initiated a hit finding campaign with the objective of discovering cyclic boronic acids as inhibitors of the β5i subunit of iCP This type of compounds is well known by medicinal chemists, and three cyclic boronic acid drugs have been approved by the FDA recently (Table 1). To the best of our knowledge, no cyclic boronates were investigated as iCP inhibitors until the present work
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