title: VR23: A Quinoline-Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E-Mediated Centrosome Amplification.
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 β2 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.
authors.affiliation: Advanced Medical Research Institute of Canada, Sudbury, Ontario, Canada. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Pundir
authors.affiliation: Advanced Medical Research Institute of Canada, Sudbury, Ontario, Canada.
authors.forename: Hai-Yen
authors.initials: HY
authors.lastname: Vu
authors.affiliation: Advanced Medical Research Institute of Canada, Sudbury, Ontario, Canada.
authors.forename: V Raja
authors.initials: VR
authors.lastname: Solomon
authors.affiliation: Advanced Medical Research Institute of Canada, Sudbury, Ontario, Canada. Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McClure
authors.affiliation: Advanced Medical Research Institute of Canada, Sudbury, Ontario, Canada. Department of Medicine, University of Ottawa, Faculty of Medicine, Ottawa, Ontario, Canada. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Northern Ontario School of Medicine, Sudbury, Ontario, Canada. hlee@amric.ca.
authors.forename: Hoyun
authors.initials: H
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D000069286:Bortezomib / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects* / Q000378:metabolism; D019927:Cyclin E / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D057149:Ubiquitinated Proteins / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000604239:7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline; D000970:Antineoplastic Agents; D019927:Cyclin E; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D011804:Quinolines; D013449:Sulfonamides; D057149:Ubiquitinated Proteins; D000069286:Bortezomib; D017239:Paclitaxel