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].
Oprozomib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human OCs
25.88 nM
21 days
To evaluate the inhibitory effect of Oprozomib on osteoclast differentiation, results showed that Oprozomib significantly inhibited the formation of osteoclasts.
Leukemia. 2013 Feb;27(2):430-40.
Human 26S proteasome
0.5 mM
30 minutes
To investigate the effect of Oprozomib on the structure of the 26S proteasome, it was found that drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP), resulting in the stabilization of a non-productive state.
Nat Commun. 2017 May 25;8:15578.
MM cell lines
50 nM
4 hours
To evaluate the cytotoxic effect of Oprozomib under transient dosing conditions, results showed that Oprozomib effectively inhibited the survival of multiple myeloma cells even after short-term exposure.
Leukemia. 2013 Feb;27(2):430-40.
Human MM cell lines
25 nM
48 hours
To evaluate the cytotoxic effect of Oprozomib on human multiple myeloma cells, results showed that Oprozomib exhibited significant cytotoxicity.
Leukemia. 2013 Feb;27(2):430-40.
Acute lymphoblastic leukemia cells
19.2 nM
96 hours
To evaluate the cytotoxic effect of ONX 0912 on acute lymphoblastic leukemia cells, the results showed that the LC50 of ONX 0912 for ALL cells was 19.2 nM.
Haematologica. 2013 Dec;98(12):1896-904.
Acute myeloid leukemia cells
93.7 nM
96 hours
To evaluate the cytotoxic effect of ONX 0912 on acute myeloid leukemia cells, the results showed that the LC50 of ONX 0912 for AML cells was 93.7 nM.
Haematologica. 2013 Dec;98(12):1896-904.
Chronic myeloid leukemia bone marrow mononuclear cells
0.15 to 0.35 μM
48 hours
To select the most efficient chemical to induce apoptosis in leukemia cells, a multi-drug screen was applied on bone marrow mononuclear cells from chronic myeloid leukemia (CML) patients. Oprozomib (Cpd 21) was chosen for the subsequent experiments.
Cancer Sci. 2021 Jan;112(1):133-143.
Oprozomib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Non-tumor bearing mice
Oral gavage
30 mg/kg
Once daily for 5 consecutive days followed by 2 days of rest for 2 weeks
To evaluate the effect of Oprozomib on bone metabolism in non-tumor bearing mice, results showed that Oprozomib significantly increased trabecular bone volume, decreased bone resorption and enhanced bone formation.
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