title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Yik Khuan
authors.initials: YK
authors.lastname: Ho
authors.forename: Paola
authors.initials: P
authors.lastname: Bargagna-Mohan
authors.forename: Marie
authors.initials: M
authors.lastname: Wehenkel
authors.forename: Royce
authors.initials: R
authors.lastname: Mohan
authors.forename: Kyung-Bo
authors.initials: KB
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D015335:Molecular Probes / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D015335:Molecular Probes; C116212:dihydroeponemycin; C071313:LMP-2 protein; D012694:Serine; D002918:Chymotrypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex