Anti-tumor activity of the proteasome inhibitor BSc2118 against human multiple myeloma

Zang, Meirong; Li, Zengjun; Liu, Lanting; Li, Fēi; Li, Xin; Dai, Yun; Li, Wei; Kuckelkorn, Ulrike; Doeppner, Thorsten R.; Hermann, Dirk M.; Zhou, Wen; Qiu, Lugui; Jin, Fengyan

doi:10.1016/j.canlet.2015.06.011

Cited by 6 publications

(6 citation statements)

References 44 publications

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“…BTZ concentrations were started at 1 nM and escalated by increments of 1 nM when culture densities doubled in cell number. 26 NEK2 overexpression BTZ-resistance MM cell lines, ARP1 and OCI-MY5 cells were constructed in our previous study. 27 All the cell lines were performed STR profiling, and grown under mycoplasma-free conditions at 37 °C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…When the tumor volume reached 2000 mm 3 the mice were euthanized in a carbon dioxide chamber. 26 , 28 Tumor formation was examined in 5 mice in each group. All procedures for in vivo studies were performed according to a protocol approved by the Animal Care and Use Committee (IACUC) of the Institute of Hematology, Chinese Academy of Medical Science, and compliance with animal use guidelines.…”

Section: Methodsmentioning

confidence: 99%

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Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Wei

Liu

et al. 2022

eBioMedicine

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Wei

Liu

et al. 2022

eBioMedicine

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“…In 2005, we identified the tripeptidic aldehyde BSc2118 ( 1 ; Scheme a) as a very potent (IC 50,β5 = 58 nM) and selective covalent CP inhibitor The special feature of 1 is a sterically demanding tert -butyl aspartate P2 residue, which discriminates inhibition against the majority of the protease environment. In a recent study, 1 shows cytotoxic effect against human tumor cells and efficacy in multiple myeloma xenografts …”

mentioning

confidence: 99%

“… The special feature of 1 is a sterically demanding tert -butyl aspartate P2 residue, which discriminates inhibition against the majority of the protease environment. In a recent study, 1 shows cytotoxic effect against human tumor cells and efficacy in multiple myeloma xenografts …”

mentioning

confidence: 99%

“…In a recent study, 1 shows cytotoxic effect against human tumor cells and efficacy in multiple myeloma xenografts. 9 In this work, we investigated a ligand recognition mechanism leading to novel insights as a function of P1 residues on inhibitory activity as well as substrate hydrolysis. Our starting hypothesis was that ligand association and dissociation is influenced by hydrophobic interactions between a substrate's P1 residue and the highly flexible side chain of Met 45 within the proteasome's β5 subunit.…”

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confidence: 99%

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Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome’s β5 Catalytic Subunit

et al. 2016

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The ubiquitin/proteasome system is the major protein degradation pathway in eukaryotes with several key catalytic cores. Targeting the β5 subunit with small-molecule inhibitors is an established therapeutic strategy for hematologic cancers. Herein, we report a mouse-trap-like conformational change that influences molecular recognition depending on the substitution pattern of a bound ligand. Variation of the size of P1 residues from the highly β5-selective proteasome inhibitor BSc2118 allows for discrimination between inhibitory strength and substrate conversion. We found that increasing molecular size strengthens inhibition, whereas decreasing P1 size accelerates substrate conversion. Evaluation of substrate hydrolysis after silencing of β5 activity reveals significant residual activity for large residues exclusively. Thus, classification of the β5 subunit as chymotrypsin-like and the use of the standard tyrosine-containing substrate should be reconsidered.

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KPT‐330 and Y219 exert a synergistic antitumor effect in triple‐negative breast cancer through inhibiting NF‐κB signaling

et al. 2023

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Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype, which has poor prognosis due to the lack of effective targeted drugs. KPT‐330, an inhibitor of the nuclear export protein CRM‐1, has been widely used in clinical medicine. Y219, a novel proteasome inhibitor designed by our group, shows superior efficacy, reduced toxicity, and reduced off‐target effects as compared to the proteasome inhibitor bortezomib. In this study, we investigated the synergistic effect of KPT‐330 and Y219 against TNBC cells, as well as the underlying mechanisms. We report that combination treatment with KPT‐330 and Y219 synergistically inhibited the viability of TNBC cells in vitro and in vivo. Further analysis revealed that the combined use of KPT‐330 and Y219 induced G2‐M phase arrest and apoptosis in TNBC cells, and attenuated nuclear factor kappa B (NF‐κB) signaling by facilitating nuclear localization of IκB‐α. Collectively, these results suggest that the combined use of KPT‐330 and Y219 may be an effective therapeutic strategy for the treatment of TNBC.

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Anti-tumor activity of the proteasome inhibitor BSc2118 against human multiple myeloma

Cited by 6 publications

References 44 publications

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome’s β5 Catalytic Subunit

KPT‐330 and Y219 exert a synergistic antitumor effect in triple‐negative breast cancer through inhibiting NF‐κB signaling

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