Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors.
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.
Affiliation: Institute of Microbial Chemistry, Numazu, Japan.Show MeSH
Related in: MedlinePlus
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).