ONX 0912 is an inhibitor ofproteasome that targets the chymotrypsin-like activity of the 20Sproteasome subunits β5 (IC50 = 36 nM) and LMP7 (IC50 = 82 nM).
The proteasome is a multicatalytic protease complex consisted of a 20S proteolytic core and two 19S regulatory caps that assemble with the core at either end to form a 26S complex. The proteasome is responsible for the ubiquitin-dependent turnover of cellular proteins and regulates cell proliferation and survival pathways. Oprozomib is a tripeptide proteasome inhibitor that selectively inhibits chymotrypsin-like activity of both the constitutive proteasome (β5) and immunoproteasome (LMP7) with IC50 values of 36nM and 82nM, respectively. In vitro, oprozomib inhibited cell viability of a pair of uterine sarcoma tumor cell lines MES(MDR-) and MES(MDR+) with IC50 values of 25nM and 1322nM, respectively[2]. Oprozomib inhibited the growth of UMSCC-1, CALL33, carfilzomib-resistant UMSCC-1 and carfilzomib-resistant CAL33 cell lines with IC50 values of 88.2nM, 59.3nM, 2294nM and 1112nM, respectively[3]. In addition, oprozomib inhibited the breast cancer cell lines MDA-MB-231 and BT-549 with IC50 values of 0.079μM and 0.05μM, respectively. Oprozomib also increased doxorubicin-induced cytotoxic effects and apoptosis by enhancing doxorubicin-induced JNK/p38/ MAPK phosphorylation in the breast cancer cell lines MDA-MB-231 and BT-549[4]. In vivo, oral administration of oprozomib at 30mg/kg resulted in more than 80% proteasome inhibition in blood, liver and adrenal gland, and elicited an antitumor response equivalent to intravenously administered carfilzomib in RL cells and CT26 cells mouse xenograft models[2].
作用机制
Oprozomib elicits potent pharmacological actions by forming a covalent
bond with the active site N-terminal threonine of the 20S proteasome.[2].
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