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Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors.

Momose I, Abe H, Watanabe T, Ohba S, Yamazaki K, Dan S, Yamori T, Masuda T, Nomoto A - Cancer Sci. (2014)

Bottom Line: Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29.We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation.Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbial Chemistry, Numazu, Japan.

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Related in: MedlinePlus

Inhibition of the proteasome by tyropeptin-boronic acid derivatives. (a) Structures of tyropeptin-boronic acid derivatives. (b) Proteasome inhibitory activity in vitro. Proteasome activities were determined by the Proteasome-Glo Assay System using purified human erythrocyte-derived 20S proteasome. (c) Accumulation of proteasome-sensitive fluorescent proteins. HEK293PS cells were incubated with inhibitors for 18 h, and fluorescent protein levels were monitored by fluorescence microscopy. (d) Accumulation of ubiquitinated proteins in human multiple myeloma cells. RPMI8226, KMS-11 and IM-9 cells were incubated with inhibitors for 6 or 24 h, and ubiquitinated proteins were detected by western blotting.
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fig01: Inhibition of the proteasome by tyropeptin-boronic acid derivatives. (a) Structures of tyropeptin-boronic acid derivatives. (b) Proteasome inhibitory activity in vitro. Proteasome activities were determined by the Proteasome-Glo Assay System using purified human erythrocyte-derived 20S proteasome. (c) Accumulation of proteasome-sensitive fluorescent proteins. HEK293PS cells were incubated with inhibitors for 18 h, and fluorescent protein levels were monitored by fluorescence microscopy. (d) Accumulation of ubiquitinated proteins in human multiple myeloma cells. RPMI8226, KMS-11 and IM-9 cells were incubated with inhibitors for 6 or 24 h, and ubiquitinated proteins were detected by western blotting.

Mentions: Previously, we identified new proteasome inhibitors, tyropeptins, which are produced by Kitasatospora sp. MK993-dF2.(22,23) Tyropeptins specifically inhibit the CT-L activity of the 20S proteasome. With the aim of enhancing the inhibitory activities of these molecules, we constructed a structural model of tyropeptin A bound to the CT-L catalytic site of the mammalian 20S proteasome. We designed new tyropeptin derivatives(24,25) and conducted structure-activity relationship (SAR) studies of these derivatives. We found that tyropeptin-boronic acid derivatives display an enhanced inhibitory activity against CT-L activity of the human proteasome.(26) These results encouraged us to perform further SAR studies of tyropeptin-boronic acid derivatives to develop derivatives more potent than bortezomib.(27) In the present study, we report the antitumor effects of tyropeptin-boronic acid derivatives AS-06 and AS-29 (Fig. 1a).


Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors.

Momose I, Abe H, Watanabe T, Ohba S, Yamazaki K, Dan S, Yamori T, Masuda T, Nomoto A - Cancer Sci. (2014)

Inhibition of the proteasome by tyropeptin-boronic acid derivatives. (a) Structures of tyropeptin-boronic acid derivatives. (b) Proteasome inhibitory activity in vitro. Proteasome activities were determined by the Proteasome-Glo Assay System using purified human erythrocyte-derived 20S proteasome. (c) Accumulation of proteasome-sensitive fluorescent proteins. HEK293PS cells were incubated with inhibitors for 18 h, and fluorescent protein levels were monitored by fluorescence microscopy. (d) Accumulation of ubiquitinated proteins in human multiple myeloma cells. RPMI8226, KMS-11 and IM-9 cells were incubated with inhibitors for 6 or 24 h, and ubiquitinated proteins were detected by western blotting.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317970&req=5

fig01: Inhibition of the proteasome by tyropeptin-boronic acid derivatives. (a) Structures of tyropeptin-boronic acid derivatives. (b) Proteasome inhibitory activity in vitro. Proteasome activities were determined by the Proteasome-Glo Assay System using purified human erythrocyte-derived 20S proteasome. (c) Accumulation of proteasome-sensitive fluorescent proteins. HEK293PS cells were incubated with inhibitors for 18 h, and fluorescent protein levels were monitored by fluorescence microscopy. (d) Accumulation of ubiquitinated proteins in human multiple myeloma cells. RPMI8226, KMS-11 and IM-9 cells were incubated with inhibitors for 6 or 24 h, and ubiquitinated proteins were detected by western blotting.
Mentions: Previously, we identified new proteasome inhibitors, tyropeptins, which are produced by Kitasatospora sp. MK993-dF2.(22,23) Tyropeptins specifically inhibit the CT-L activity of the 20S proteasome. With the aim of enhancing the inhibitory activities of these molecules, we constructed a structural model of tyropeptin A bound to the CT-L catalytic site of the mammalian 20S proteasome. We designed new tyropeptin derivatives(24,25) and conducted structure-activity relationship (SAR) studies of these derivatives. We found that tyropeptin-boronic acid derivatives display an enhanced inhibitory activity against CT-L activity of the human proteasome.(26) These results encouraged us to perform further SAR studies of tyropeptin-boronic acid derivatives to develop derivatives more potent than bortezomib.(27) In the present study, we report the antitumor effects of tyropeptin-boronic acid derivatives AS-06 and AS-29 (Fig. 1a).

Bottom Line: Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29.We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation.Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbial Chemistry, Numazu, Japan.

Show MeSH
Related in: MedlinePlus