LMP2-Specific Inhibitors: Chemical Genetic Tools for Proteasome Biology

Abstract

The immunoproteasome, having been linked to neurodegenerative diseases and hematological cancers, has been shown to play an important role in MHC class I antigen presentation. However, its other pathophysiological functions are still not very well understood. This can be attributed mainly to a lack of appropriate molecular probes that can selectively modulate the immunoproteasome catalytic subunits. Herein, we report the development of molecular probes that selectively inhibit the major catalytic subunit, LMP2, of the immunoproteasome. We show that these compounds irreversibly modify the LMP2 subunit with high specificity. Importantly, LMP2-rich cancer cells compared to LMP2-deficient cancer cells are more sensitive to growth inhibition by the LMP2-specific inhibitor, implicating an important role of LMP2 in regulating cell growth of malignant tumors that highly express LMP2.

Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

“…Bortezomib, which targets the constitutive proteasome and immunoproteasome, is the first clinically approved proteasome inhibitor for relapsed and/or refractory myeloma and mantle cell lymphoma (34). Recently, novel proteasome inhibitors preferentially targeting subunits of the immunoproteasome were described (22,(35)(36)(37)). An LMP2-specific inhibitor attenuated proliferation in myeloma patient samples and other hematologic malignancies, although the chymotrypsin-like activity associated with the subunits b5 and b5i was also reduced at the concentrations used (37).…”

Targeting the Ubiquitin-Proteasome System in Heart Disease: The Basis for New Therapeutic Strategies

“…The precise activity conferred by b1i incorporation appears controversial in reporter assays, potentially due to co-incorporation of b2i (77). However, a b1i-specific inhibitor reduces chymotrypsin-like activity and hydrophobic substrate preference of b1i is supported by protein crystallography (97,103). Similar to b2 and b5, subunits b2i and b5i preferentially cleave polypeptides after alkaline and hydrophobic amino acids, respectively (68,103).…”

“…Resistance is overcome, at least in part, by carfilzomib (90), a peptidyl-epoxyketone that targets similar proteasome activities such as bortezomib, but binds irreversibly to proteolytic sites (122). Lessening adverse effects may be achieved by targeting those proteasome subpopulations that are most abundant in target cells (97,121,151). For example, the inhibitors IPSI-001 and PR-957 preferentially target inducible proteasome subunits (122), such as b5i (103).…”

“…Allosteric drugs may have distinct advantages compared with irreversible and competitive proteasome inhibitors, such as higher versatility in targeting sites, but proteasome allostery is poorly understood (67). For research and clinical purposes, further specialization of inhibitors to differentiate between proteasome subpopulations is an ongoing endeavor with major achievements being accomplished over the past few years (97,103,121,151). Differential targeting of proteasome subpopulations by current proteasome inhibitors is feasible, but lacks precision (117).…”

Methyl Aryloxy Gallates as Regulators of Vascular Smooth Muscle Cell Proliferation

“…It has been reported that a TBSprotected compound showed excellent biological activity. 6 Direct comparison of catechol 6c and dimethoxy 5c revealed that catechol moiety is essential to exhibit anti-proliferative activity. Only 4-chloro analog 5i retained activity among dimethoxy derivatives, thus we hypothesize it could have different binding mode.…”