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RESEARCH ARTICLE
A focused structure–activity relationship study of
psoralen-based immunoproteasome inhibitors†
Cite this: Med. Chem. Commun.,
2019, 10, 1958
a
a
Eva Shannon Schiffrer,a Izidor Sosič, a Andrej Šterman,
Janez Mravljak,
Irena Mlinarič Raščan,b Stanislav Gobeca and Martina Gobec
b
*
The immunoproteasome is
a multicatalytic protease that is predominantly expressed in cells of
hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types
of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with
non-peptidic scaffolds remains a challenging task. Here, we describe a focused series of psoralen-based
inhibitors of the β5i subunit of the immunoproteasome with different substituents placed at position 4′.
The most promising compound was further evaluated through changes at position 3 of the psoralen ring.
Despite a small decrease in the inhibitory potency in comparison with the parent compound, we were able
to improve the selectivity against other subunits of both the immunoproteasome and the constitutive
proteasome. The most potent compounds discriminated between both proteasome types in cell lysates
and also showed a decrease in cytokine secretion in peripheral blood mononuclear cells.
Received 17th July 2019,
Accepted 8th September 2019
DOI: 10.1039/c9md00365g
rsc.li/medchemcomm
lymphoma.6 However, the clinical use of such conventional,
non-selective proteasome inhibitors is often limited due to
Introduction
The heart of the ubiquitin–proteasome system, the 26S
proteasome, is responsible for the regulation of various cell
processes and the maintenance of protein homeostasis in cells.
It is the most important non-lysosomal proteolytic complex
degrading misfolded or damaged proteins.1 The 26S
proteasome consists of a 20S core and 19S regulatory sections,
with the 20S core comprising three active subunits with distinct
catalytic activities, i.e. β1 (caspase-like), β2 (trypsin-like), and
β5 (chymotrypsin-like).2,3 Two major types of 20S cores exist in
vertebrates: the constitutive proteasome (cCP), expressed in all
cell types, and the immunoproteasome (iCP), expressed mostly
in hematopoietic cells. The latter can also be found in other
cell types upon induction by the tumour necrosis factor-α and
interferon-γ during acute immune and inflammatory
responses.4,5 Of note, in the iCP, the catalytically active
subunits β are replaced by their β1i, β2i, and β5i counterparts.
Extensive research in the proteasome field in the last two
decades resulted in the development of non-selective
proteasome inhibitors, such as bortezomib and carfilzomib,
used in the treatment of multiple myeloma and mantle-cell
the side effects caused by the non-selective inhibition of
protein degradation.7 While the cCP is expressed in all
eukaryotic cells, the iCP expression is mostly upregulated
during the course of disease processes,8–10 leading to the
assumption that its selective inhibition is expected to cause
fewer side effects. The latest studies showed that co-
inhibition of two subunits of the iCP is required to show
beneficial effects in autoimmune diseases, i.e. either by
combining β1i- and β5i-selective inhibitors in a synergistic
approach11 or with
a single molecule that is able to
simultaneously inhibit two catalytically active subunits of the
iCP.12 The excellent work by the groups of Overkleeft,13,14
Groll,15 Lin,16,17 and Johnson12,18 yielded selective inhibitors
of all subunits of the iCP (Fig. 1) and these represent both
very valuable molecular tools in the studies of iCP biology
and lead compounds towards new drugs (Fig. 1). It is
noteworthy that KZR-616, a β1i- and β5i-targeting compound,
is currently being evaluated in clinical studies for the
treatment of autoimmune and inflammatory diseases.12,19
From a structural perspective, the majority of these
inhibitors of the iCP have a peptidic backbone, and are thus
prone to poor metabolic stability and low bioavailability
leading to lack of oral exposure.20,21 With an attempt to
circumvent these limitations, several lines of research by
various groups are devoted to the development of non-
peptidic inhibitors of the iCP (Fig. 2).22–26 Despite this, the
number of such inhibitors is scarce and, interestingly, only
inhibitors of the β5i subunit were discovered so far.
a Faculty of Pharmacy, Chair of Pharmaceutical Chemistry, University of
Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
b Faculty of Pharmacy, Chair of Clinical Biochemistry, University of Ljubljana,
Aškerčeva 7, 1000 Ljubljana, Slovenia. E-mail: martina.gobec@ffa.uni-lj.si;
Tel: +386 1 476 9636
† Electronic supplementary information (ESI) available: General chemistry
methods, all biochemistry experimental data, spectroscopic analyses, and
representative NMR, HPLC, and HRMS spectra. See DOI: 10.1039/c9md00365g
1958 | Med. Chem. Commun., 2019, 10, 1958–1965
This journal is © The Royal Society of Chemistry 2019