VR23: A Quinoline-Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E-Mediated Centrosome Amplification.
Cancer Res
; 75(19): 4164-75, 2015 Oct 01.
Article
in En
| MEDLINE
| ID: mdl-26238784
ABSTRACT
The proteasome is clinically validated as a target for cancer therapeutics. However, proteasome-inhibitory agents that are cancer selective have yet to be developed. In this study, we report the identification of a safe and effective proteasome inhibitor with selective anticancer properties. We screened a chemical library constructed using a hybrid approach that incorporated a 4-piperazinylquinoline scaffold and a sulfonyl phamarcophore. From this library, we identified 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (VR23) as a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC50 = 1 nmol/L), chymotrypsin-like proteasomes (IC50 = 50-100 nmol/L), and caspase-like proteasomes (IC50 = 3 µmol/L). Data from molecular docking and substrate competition assays established that the primary molecular target of VR23 was ß2 of the 20S proteasome catalytic subunit. Notably, VR23 was structurally distinct from other known proteasome inhibitors and selectively killed cancer cells by apoptosis, with little effect on noncancerous cells. Mechanistic investigations showed that cancer cells exposed to VR23 underwent an abnormal centrosome amplification cycle caused by the accumulation of ubiquitinated cyclin E. In combinations with the clinically approved chymotrypsin-like proteasome inhibitor bortezomib, VR23 produced a synergistic effect in killing multiple myeloma cells, including those that were resistant to bortezomib. VR23 was effective in vivo in controlling multiple myelomas and metastatic breast cancer cells, in the latter case also enhancing the antitumor activity of paclitaxel while reducing its side effects. Overall, our results identify VR23 as a structurally novel proteasome inhibitor with desirable properties as an anticancer agent.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quinolines
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Sulfonamides
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Antineoplastic Combined Chemotherapy Protocols
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Centrosome
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Cyclin E
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Ubiquitinated Proteins
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Molecular Targeted Therapy
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Proteasome Inhibitors
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Neoplasm Proteins
/
Antineoplastic Agents
Language:
En
Journal:
Cancer Res
Year:
2015
Document type:
Article
Affiliation country:
Canada