Syrbactin proteasome inhibitor TIR-199 overcomes bortezomib chemoresistance and inhibits multiple myeloma tumor growth in vivo. (January 2020)

• Record Type: Journal Article
• Authors: Pierce, Marquicia R.; Robinson, Reeder M.; Ibarra-Rivera, Tannya R.; Pirrung, Michael C.; Dolloff, Nathan G.; Bachmann, André S.
• Is Part Of: Leukemia research. Volume 88(2020)
• Publication Date: 2020-01
• Subjects: Chemoresistance -- Multiple myeloma -- Mantle cell lymphoma -- TIR-199 -- Syrbactin -- Proteasome inhibitors; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2019.106271
• Languages: English
• ISSNs: 0145-2126

Abstract

Graphical abstract: Highlights: TIR-199 is a syrbactin natural product analog and belongs to a new structural class of irreversible proteasome inhibitors. TIR-199 overcomes chemoresistance to bortezomib in multiple myeloma and mantle cell lymphoma. TIR-199 reduced the tumor burden in a multiple myeloma mouse model. Abstract: Multiple myeloma (MM) and mantle cell lymphoma (MCL) are blood cancers that respond to proteasome inhibitors. Three FDA-approved drugs that block the proteasome are currently on the market, bortezomib, carfilzomib, and ixazomib. While these proteasome inhibitors have demonstrated clinical efficacy against refractory and relapsed MM and MCL, they are also associated with considerable adverse effects including peripheral neuropathy and cardiotoxicity, and tumor cells often acquire drug resistance. TIR-199 belongs to the syrbactin class, which constitutes a novel family of irreversible proteasome inhibitors. In this study, we compare TIR-199 head-to-head with three FDA-approved proteasome inhibitors. We demonstrate that TIR-199 selectively inhibits to varying degrees the sub-catalytic proteasomal activities (C-L/β1, T-L/β2, and CT-L/β5) in three actively dividing MM cell lines, with Ki50 (CT-L/β5) values of 14.61 ± 2.68 nM (ARD), 54.59 ± 10.4 nM (U266), and 26.8 ± 5.2 nM (MM.1R). In most instances, this range was comparable with the activity of ixazomib. However, TIR-199 was more effective than bortezomib, carfilzomib, and ixazomib in killing bortezomib-resistant MM and MCL cell lines, as judged by a low resistance index (RI) between 1.7 and 2.2, which implies that TIR-199 indiscriminately inhibits both bortezomib-sensitive and bortezomib-resistant MM and MCL cells at similar concentrations. Importantly, TIR-199 reduced the tumor burden in a MM mouse model (p < 0.01) confirming its potency in vivo . Given the fact that there is still no cure for MM, the further development of TIR-199 or similar molecules that belong to the syrbactin class of proteasome inhibitors is warranted.